TWI379682B - Conveniently implantable sustained release drug compositions - Google Patents

Description

1379682 IX. INSTRUCTIONS OF THE INVENTION · TECHNICAL FIELD OF THE INVENTION The present invention provides various pharmaceutical formulations for biocompatible and biodegradable injection liquids, implantable solids, and injectable steroids for treating the whole body and For local conditions. [Prior Art]

Current drug delivery modes' such as topical administration, oral delivery and intramuscular, intravenous and subcutaneous injections' may cause high/low blood concentrations and/or short half-life of the drug in the blood. In some cases, when these standard methods of administration are used to achieve therapeutic efficacy, considerable drug doses are required, which may cause toxic side effects. Efforts have been made to study techniques for controlling drug release to avoid certain risks of traditional treatments. The goal is to deliver the drug in a continuous and continuous manner. In addition, the method of locally controlling drug release has tissue site or organ specificity.

In response to these issues, we have developed reservoir delivery systems » drug delivery systems that are not biodegradable, including 'Vitrasert® (Bausch & Lomb)', a kind of intraocular delivery of viral inhibitors. (ganciclovir) surgical implant; Duros® (Durect Corp.), a surgical implantable osmotic pump for delivery of leuprolide actetate for the treatment of advanced prostate cancer; Implanon® (produced by Organon International), a subcutaneous contraceptive implant. 5 5 1379682 Biodegradable implants include, for example, Lupron Depot (manufactured by TAP Pharmaceutical Prods., Inc.), which is a sustained release microcapsule injection of a luteinizing hormone releasing hormone (LH-RH) analog, For the treatment of prostate cancer; the dexamethasone anterior chamber drug delivery system (produced by Oculex Pharmaceuticals, Inc.) under the trade name of Surodex®; and the trade name Nutropin Depto® (manufactured by Genentech), a coating of polylactic acid/ Gene recombinant human growth hormone microparticles in polylactide-coglycolide (PLG) microspheres.

In addition, polyethylene glycol conjugates (or PEGylation) are currently being used to reduce the frequency of administration. For example, Macugen® (produced by Eyetech Pharmaceuticals, Inc.), which is applying for a US Food and Drug Administration-approved license, is a polyethylene-derived anti-VEGF aptamer. For the treatment of wet macular degeneration.

There is therefore a need for a more economical, viable and efficient method' to produce a drug delivery system that can be applied to a topical or systemic form in the form of a solid, semi-solid, liquid, etc. formulation. SUMMARY OF THE INVENTION It is an object of the present invention to provide an economical, viable and efficient drug delivery system. According to the present invention, the drug delivery system is easy to manufacture, facilitates delivery to a designated site, and is both biocompatible and biodegradable. More specifically, the formulations of the present invention provide several novel therapeutic agents that can be easily manipulated and injected or implanted by qualified medical personnel. These formulations deliver a therapeutically effective, non-toxic dose of the active drug at a primary implant over a period of 5 6 1379682. These formulations are all biocompatible and biodegradable and disappear harmlessly after delivery of the active drug to the designated location. One embodiment of the present invention provides a pharmaceutical formulation for implanting a patient to continuously release an active drug comprising a biocompatible and biodegradable adjuvant and an active drug or a pharmaceutically acceptable salt thereof. In another aspect of the invention, the formulation can be implanted into the body by injection.

Another embodiment of the present invention provides a pharmaceutical formulation for implanting a patient to continuously release an active drug, the pharmaceutical formulation comprising a biocompatible and biodegradable adjuvant and an active drug or a pharmaceutically acceptable drug thereof Accepted salts wherein the formulation exhibits an in vitro or in vivo dissolution profile releases from about 2% to about 100% of the active drug over a period of from about 1 day to about 365 days.

In yet another embodiment, a pharmaceutical formulation for implanting a patient for sustained release of an active drug comprising a biocompatible and biodegradable adjuvant and an active drug or a pharmaceutically acceptable agent thereof is provided The salt, wherein about 2% to about 60% of the active drug is released during a period of from about 1 day to about 105 days. Alternatively, about 2% to 100% of the active drug may be released over a period of about 25 days or alternatively, from about 2% to about 85% may be released during the 30 to 60 day period. Active drug. In another embodiment, from about 20% to about 60% of the active drug is released over a period of between about 80 days and 100 days. In another aspect of the invention, the formulation comprises an active agent at a concentration of between about 5% and 50% of the implant, and comprising a biocompatible and biologic 7 1379682 solvable adjuvant, The concentration of the adjuvant is at least 5% of the implant.

In another embodiment, the biocompatible and biodegradable adjuvant may be a tocopherol isomers (or vitamin E) and esters thereof, tocotrienols and its 8 Benzyl alcohol, benzyl benzoate, poly(oxyethylene) diol dibenzoate, dimethyl sulfone, Low-water-soluble poly(propylene) diol, monoester or diester formed from 〇-acetylcitric acid and linear or branched aliphatic alcohols of C] to C丨〇 In the group consisting of triesters and liquid or semi-solid polycarbonate oligomers.

One aspect of the present invention provides a controlled and sustained release drug delivery system for the posterior chamber of the eye comprising a biocompatible and biodegradable liquid matrix that is directly injectable. More specifically, this aspect of the invention provides a composition comprising dexamethasone or acetone triamcinolone acetonide and benzyl benzoate. In another aspect of this embodiment, dexamethasone is released in the vitreous of the eyeball over a period of about 60 to 90 days, between about 20 micrograms/ml and less than 1. micrograms per milliliter of winter. Or acetone triamcinolone. The active drug which can be used in the embodiments of the present invention is selected from the group consisting of analgesics, anesthetics, narcotics, angiostatic steroids, anti-inflammatory steroids. Anti-inflammatory steroids, angiogenesis inhibitors, nonsteroidal anti-inflammatories, anti-infectives 5 1379682

(anti-infective agents), anti-fungals, anti-malarials, anti-tublerculosis agents, anti-virals, alpha-type males Alpha androgenergic agonists, beta adrenergic blocking agents, carbonic anhydrase inhibitors, mast cell stabilizers, miotics Prostaglandins (pr.ostaglandins), antihistamines, antimicrotubule agents, antine ο p 1 astic agents, antipoptotics, chains Aldose reductase inhibitors, antihypertensives, antioxidants, growth hormone agonists and antagonists, vitrectomy agents, adenosine nucleoside receptors Adenosine receptor antagonists, adenosine deaminase inhibitors, cooling antagonists (gly Necessary antagonists), anti aging peptides, topoisemerase inhibitors, anti-metabolites, alkylating agents, antiandrogens , anti-oestogens, oncogene activation inhibitors telomerase inhibitors, antibodies or partial antibodies, antisense oligonucleotides ), fusion proteins ' luteinizing hormone 9 5 1379682

Luteinizing hormone releasing hormones agonists, gonadotropin releasing hormone agonists, tyrosine kinase inhibitos, epidermal growth factor inhibitors Epidermal growth fator inhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2 therapeutics, neurotensin antagonists, Peripheral sigma ligand, endothelin ETA/receptor antagonists, hypoglycemic agent

(antihyperglycemics), anti-glaucoma agents, anti-chromatin modifying enzymes, insulin, glucagon-like-peptides, weight control drugs (obesity) Management agents), anemia therapeutics, emesis therapeutics, neutropaenia therapeutics, tumor-induced hypercalcaemia therapeutics 'blood anticoagulants, immunosuppressive agents, tissue repair agents, psychotherapeutic agents, botulinum toxins (trade name Botox, by Allergan) The company produces) and nucleic acids such as small interfering RNA or RNAi. 6 1379682 [Embodiment] It is to be understood that the invention is not limited to the specific methods, procedures, and reagents described herein, and that the methods, procedures, and reagents can be varied. The terminology used herein is for the purpose of describing the particular embodiments, and is not intended to limit the scope of the invention, and the scope of the invention is defined by the scope of the appended claims.

The singular terms "a", "an" and "the" are used in the specification and the meaning of the claims. Thus, for example, reference examples that may be referred to by one adjuvant represent one or more of such types of adjuvants, including equivalents familiar to those skilled in the art. Except for the data exemplified in these operating examples, or unless otherwise stated, all numbers used in the text to indicate the amount of ingredients or reaction conditions are modified in all examples by the word "about". . When the word "about" has a percentage, it may be the mean ± 1%.

All of the mentioned patents and other published documents are hereby incorporated by reference for their disclosure, for example, the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the present disclosure. These publications only disclose the technology prior to the filing date of the present application. The inventor of the present invention should not be considered to have the right to claim the content disclosed by the earlier disclosure or other reasons. This application is filed with Vemon G. Wong and Louis L et al., January 1, 2004, entitled "Conveniently Implantable Sustained Pharmaceutical Composition (Conveniently Implantable Sustained 5 1379682).

Release Drug Compositions) US Patent Provisional Application No. 60/614,484, and Vemon G. Wong and Louis L. Wood et al., August 18, 2005, entitled "Convenient Implantable Sustained Release Pharmaceuticals" U.S. Patent Provisional Application No. 60/709,665, the entire disclosure of which is incorporated herein by reference.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the invention pertains.

The present invention is directed to a variety of novel biocompatible and biodegradable sustained release formulations. In one aspect of the invention, these formulations are injectable liquids, mechanically attachable solids, injectable colloidal or emulsified micronized particles (oil-in-water or water-in-oil). These liquid, solid and colloidal formulations are characterized by the ability to maintain a single mass or small shape at their placement. That is, these formulations do not suffer from the problem of disintegration into numerous smaller droplets or granules leaving their designated placements causing an increase in surface area that substantially alters the predetermined release rate of these drug components. The formulations of the present invention provide several novel therapeutic agents that are conveniently handled and injected or implanted by a qualified medical professional. These formulations deliver a therapeutically effective and non-toxic amount of active drug primarily at the implant site during the desired extended period. These formulations are all biocompatible and biodegradable and can be eliminated harmlessly after delivery of the active drug to a designated location. The present invention generally relates to (but not all) limited solubility (Hmited 12 5 1379682)

Soluble), the use of biocompatible and biodegradable formulations (hereinafter referred to as LSBB), which are injectable 'control and persistence of a composition for an active drug or multiple active drugs freed. A solid, colloidal or injectable controlled sustained release system can be made by combining LSBB with an active drug. These systems may incorporate more than one biodegradable component, as well as more than one active drug. The solid dosage form for implantation can be produced by ingot casting, injection molding or extrusion molding. Colloidal dosage forms can be prepared by vigorous turbulence or mechanical mixing methods. The injectable formulation can be prepared by premixing the LSBB with the active drug in a syringe or by mixing the L S B B with the active drug at or before use. The formulation may act as a coating on a stent or other implant, such as by soaking the stent in a liquid form of the formulation, followed by drying the stent.

In one aspect of the invention, novel formulations of biocompatible and biodegradable injectable liquids, implantable coacervates and injection gels are conveniently placed on the human or animal body surface or in vivo for sustained release. Active pharmaceutical agents, which can be formulated by mixing one or more adjuvants with various current or new inventive drugs such as benzyl alcohol, benzoic acid T vinegar, dibenzoic acid Diethylene glycol dibenzoate, triethylene glycol dibenzoate, diphenyl formed from poly(oxyethylene) diol having a molecular weight of about 400 mwt Formate, propylene glycol dibenzoate, dipropylene glycol dibenzoate, tripropylene glycol dibenzoate 13 1379682 (tripropylene glycol dibenzoate), by molecular weight Dibenzoate formed by poly(oxypropylene) diols of 3〇〇〇mwt, poly(propylene ether) glycol with a molecular weight of about 3000 mwt, dimethyl sulfone ) Various isomers reproductive health, reproductive numerous acetate (tocopherol acetate), ikitsuki 8 ^ D - vinegar (tocopherol succinate), alcohols women tocotrienol isomer (tocotrienol isomers) and dark

Classes, perfluorohexanes, polymeric polycarbonate oligomers', and monoesters and diesters formed from citric acid and (or to C10 linear or branched fatty alcohols) Triesters. In another aspect of the invention, the solid dosage form typically contains from about 1% to about 60% LSBB; the knee dosage form typically comprises from about 20% to about 80% LSBB; and an injectable dosage form (probably The colloidal or liquid form) typically contains from about 30% to about 99.9% LSBB.

The liquid or solid LSBB can be implanted using surgery, trocar or needle introduction. It can be placed in a body cavity by conventional methods in the art 'for example, by Cardone & Tallia in the journal Am. Family Physician, 66(2), 283-92 (2002); 66(11), 2097 -100 (2002); 67(10), 2147-52 (2003); 68(7), 1356-62 (2003); 67(4), 745-50 (2 00 3) Know the method of placing it into the joint; in the eyeball (such as in the posterior segment of the eye and in the anterior chamber of the eye); implanted into the prostate tumor by intratumoral injection (usually using a similar method to Jacks〇n et al. in the journal Cancer Res., 60(5), 4146-51 (2000) steps; implanted into a 5 1379682 tumor that cannot be surgically removed, such as glioma, by intratumoral injection (usually used similar to Emerich et al. Journal of Pharm Res, 767-75, 1 7(7), (2000); injection or insertion into an intervertebral disc or intercavity cavity; injection into the abdominal cavity or intranasal, intraspinal, subcutaneous Or intramuscular injection; injection into the subdural space of the epidural, subdural and / or arachnoid; or can be directly injected or inserted into the cerebrospinal fluid through the spinal canal or placed Box nervous ventricular system.

Furthermore, for topical active drug delivery, the system of the present invention can be surgically implanted at or near the site of action. In this way, it may be useful for treating diseases such as eye diseases, primary tumors, wind symptoms, arthritic conditions and chronic pain. The present invention also contemplates that these LSBB/active pharmaceutical compositions can be administered to, but are not limited to, the following human or animal body systems, including: muscle, bone, nervous system, autonomic nervous system, vascular system, lymphatic system, digestion System, respiratory system, urinary system, female reproductive system, male reproductive system, endocrine system or interstitial, as well as a variety of continuous and effective therapeutic agents.

Specific areas of the human or animal body that can be used for injection, implantation or topical administration of these LSBB/active pharmaceutical compositions include, but are not limited to, the heart, brain, spinal nerves, spine, skull, neck, head, eyes Hearing and balance of ear organs, nose, throat, skin, internal organs, hair, shoulders 'elbows, hands, wrists, buttocks, knees, ankles, feet, teeth, gums, liver, pancreas, prostate (prostate, or Prostate), testicular, ovary, thymus, adrenal gland, pharynx, larynx, bone, bone marrow, stomach, intestine 'upper and lower intestines, bladder, lungs, breasts. The method of surgically implanting the eye is well known to those skilled in the art, for example, in U.S. Patent Nos. 6,699,493, 6,726,918, 6, 331, 313, 5, 824, 072, 5, 766, 242, 5, 443, 505, 5, 164, 188, 4, 997, 652 and 4, 853, 224.

For example, the solid LSBB can be directly implanted into parenchymal tissues such as the brain, the spine, and any part of the central nervous system, the kidneys, the liver, the spleen, the pancreas, the lymph nodes, and the tumor. The gelatinous LSBB system can be applied to surface tissue such as skin, or absorbed as a coating on the surface of a parenchymal organ, or can be applied directly to the cornea, conjunctiva or sclera to deliver the active drug to the surface of the eye and to the interior of the eye. . Injectable LSBB is less invasive and can be injected into the eye through a needle such as a gauge 30, or can be injected through a larger needle into a body cavity such as a joint.

The system according to the present invention is particularly useful in the control and sustained release of active agents, which provides controlled and sustained release of the active drug to effectively achieve the desired local or systemic physiology or pharmacy in at least one of the following areas. Effects, including: treatment of malignant primary tumors, chronic pain, arthritis, rheumatism, hormone disorders such as diabetes and dwarfism, for immune response such as prevention or treatment of transplant rejection and cancer treatment Adjustment and so on. The system is also suitable for the treatment of HIV-related opportunistic infections such as cytomegalovirus (CMV), toxoplasmosis, Pneumocystis carinii, and Mycobacterium tuberculosis. The system can be used to deliver an active drug that is effective in treating oral mold infections. If used for such purposes, the system can be designed to fit into the shape of the tooth. LSBB for the treatment of such as glaucoma, proliferative vitreoretinopathy, diabetic retinopathy, uveitis, retinal edema, venous resistance (f) 16 1379682

It is also helpful in plugs, macular degeneration, Irvine-Gass Syndrome and cytomegalovirus retinitis, corneal diseases such as keratitis, and eye diseases such as corneal transplantation and rejection. These formulations can also be formulated to control the release of eye drops for dry eye or to control the immune response. In controlling immune responses, these formulas may contain cyclosporine, sirolimus or tacrolimus » other ocular uses including glaucoma treatment (eg, containing dimuco) (timolol) formula), antibiotic medication or anti-proliferative medication, such as 'paclitaxel'. Other uses of the formulation include, for example, the use of formulations containing sirolimus or cyclosporin to modulate allogeneic rejection (hom〇graft rejection). The topical cancer therapeutic agent can be delivered to a place such as the kidney or liver using a formulation containing, for example, adriamycin (commonly known as cranberry) or a small epidermal growth factor. Prostate cancer can also be treated with a formulation containing fenasteride. Heart stent implants, central nervous system implants (e.g., spinal implants), orthopedic implants, and the like can also be coated with a formulation containing growth/differentiation factors, anti-inflammatory agents, or antibiotics. The techniques of the present application help to overcome some of the difficulties associated with the administration of high doses of drugs to achieve toxic side effects in order to achieve an effective therapeutic effect. An important example of such a problem is the current intraocular injection of microcrystalline acetone triamcinolone (TA). See J0nas et al. in the journal Pr〇g Retin Eye Res_ 24(5) 587-611 (2005). As described in the eye, the microcrystalline acetone triamcinolone (TA) is administered intraocularly to treat diseases such as intraocular angiogenesis, ocular edema or inflammation, and the above references are included herein for reference 17 1379682

test. The treatment requires placing a solution containing the appropriate concentration of bismuth in the vitreous cavity for up to one month to one year or even longer. And τα is in the vitreous body; the treatment is about 1.5 μg/ml or lower (Matsuda et al., 46)

Invest Ophthalmol Vis Sci. 1062-1068 (2005)), but when the sputum concentration exceeds 10 μg/ml for a long period of time, it may cause harmful complications such as glaucoma, cataract, and cytotoxicity. (See Gillies et al., 122(3) Arch Ophthalmol. 336-340 (2004); Jonas et al., 15(4) Eur J Ophthalmol. 462-4 (2005); Yeung et al, 44 Invest Ophthalmol Vis Sci 5293-5300 (2003)) ° The number of restrictions on the administration of TA can be limited to one or two injections per year (generally patients may be accompanied by endophthalmitis, see Bucher et al., 123(5) Arch Ophthalmol. 649-53 ( 2005)), but this will conflict with the ability to provide sufficient amounts of crystallization without causing toxic concentrations. The novel composition of the present invention, by containing a specified amount of cerium crystals in an injectable biocompatible/biodegradable medium, can continuously control the release of safe therapeutic doses in the eye for up to 6 months or more. The problem has been solved for a long time. Further discussion of eye diseases, the metabolism of the posterior chamber of the eye and the symptoms of inflammation have been extremely difficult to treat. Proliferative vitreoretinopathy (PVR), uveitis, cystic macular edema (CME), diabetes and macular degeneration are the leading causes of blindness. Traditional methods of drug delivery include topical, intraocular, subconjunctival, or systemic administration, but most of them have limited efficacy due to poor drug penetration (due to blood-eye barrier obstruction) and toxic side effects. An effective method for delivering drugs to the posterior chamber of the eye 18 1379682

Place the drug directly in the vitreous cavity. Intravitreal drug injections are effective in the human body and in the human body, but it is necessary to repeatedly and frequently inject the therapeutic concentration of the drug. For example, direct injection of corticosteroids, particularly acetone triammonolone, is particularly effective in the treatment of designated wet macular degeneration and diabetic omental edema. Due to the short half-life of the drug in the eye, frequent injections are required. In addition, the drug is made into a bolus (or bolus), so it is uncontrollable that the concentration of the drug is high first and then low. As a result, adverse effects such as infection, glaucoma, and cataract formation often occur. Vitrasert® (Bausch & Lomb) is a drug storage system that lasts for 8 months to treat cytomegalovirus retina with an antiviral agent, gancyc 1 〇vir. inflammation. The system is a biodegradable system that must be accessed and removed by surgery. Similarly, the trade name P〇surdex® (AllerganPhanna is a one-month biodegradable delivery system that requires surgery into the eyeball containing dexamethasone and polylactic acid-glycolic acid (PLGA) to treat the eye. A posterior chamber disorder. Accordingly, an embodiment of the present invention provides an eyeball control and sustained release drug delivery system for the posterior segment of the eye. The system is biodegradable and biocompatible with a microdispersible drug or a mixture of drugs. It consists of a liquid matrix and can be directly injected into the posterior segment of the eye with a relatively small needle. The drug delivery time can be as short as several days, up to several months, up to a year or more; The matrix will slowly and safely disappear with time, so there is no need to remove it. An exemplary embodiment t contains the ground object with the west view of the block, and the plant is the inner split to the whole race.

19 1379682 Miso and benzyl benzoate. In this system, a 50 microliter (μ] 1 delivery of dexamethasone containing a 25% intravitreal dose has an average vitreous concentration of about 8 μg/ml over a period of 3 months. In contrast, the 25 microliter injection volume delivered an average intravitreal concentration of about 4_0 micrograms/ml over a 6 day period. This composition is biocompatible, biodegradable, non-toxic, easy to manufacture, simple to deliver, and capable of elastically adjusting the therapeutic dose and delivery period.

Many other diseases are familiar to those of ordinary skill in the field, such as Goodman & Oilman in the literature THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (McGraw Hill, 2001) and the literature REMINGTON'S PHARMACEUTICAL SCIENCES (Lippincott Williams &Wilkins; 20th ed., These conditions are described in 2000). Those of ordinary skill in the art can determine which diseases are suitable for use in the present invention without unnecessary experimentation.

Suitable classes of active drugs that can be used in the system according to the invention include, but are not limited to, the following drugs: | peptides and proteins, such as cyclosporin, insulins, glucagon-like peptides (glucagon-like- Peptides), growth hormones, insulin related growth factors, botulinum toxin (Botox, Allergan), and heat shock proteins (heat shock proteins); anesthetics And analgesics such as lidocaine and its related compounds with benzodiazepam and its related compounds; (!) 20 1379682 anticancer drugs such as 5-fluorouracil, methylamine Meth (methotrexate) and its related compounds;

Anti-inflammatory agents, such as 6-mannose phosphate; anti-fungal agents, such as fluconazole and related compounds; antiviral agents such as trisodium phosphomonoformate, Trifluorothymidine, acyci〇vir, cidofovir, gancicl〇vir, DDI and AZT; cell transport/mobility retarders Impending agents, such as colchicines, vincentine (Vincristine), cytochalasin B and related compounds; anti-glaucoma agents, such as dimuco, betshulo (beta X 〇丨ο 1), beta-blockers such as atenolol; immune response modifiers such as muramyi dipeptide and related compounds;

Steroid compounds such as dexamethasone, prednisolone and related compounds; and Carbonic anhydrase inhibitors. In addition to the above agents, other drugs suitable for administration, particularly for use on the tissues surrounding the eye or the eye to produce a local or systemic physiological or pharmaceutical effect, may also be used in the system according to the present invention. Examples of such agents include antibiotics such as tetracycline, chloramphenicol, ciprofloxacin, penicillin (or penicillin, ampicillin). 5 1379682 Any pharmaceutically acceptable form of the active agent described herein may also be used in the practice of the invention, e.g., the free base form of the active agents, or a pharmaceutically acceptable salt or ester. Pharmaceutically acceptable salts include, for example, sulfates, lactates, acetates, fatty acid salts, hydrogen hydrochlorides (hydrochlorides), tartrates, maleates, citrates, phosphates, and the like. .

The active agents may also be combined with other pharmaceutically acceptable carriers and several additional ingredients such as antioxidants, stabilizers, diffusion enhancers and the like. For example, when it is undesirable to ingest the active drug, the active drug can be formulated in a hydrophobic carrier such as a wax or oil to allow successful diffusion of the active drug from the system. Such carriers are well known to those skilled in the art.

In another aspect of the invention, a low solubility active drug can be used in combination with a biodegradable and biocompatible adjuvant having a higher solubility to produce an LSBB formulation. For example, dimethyl sulfone can be used as a binder in the LSBB formulation of a limited solubility active drug. Therefore, the use of soluble adjuvants in a LSBB formulation is also within the scope of the invention. In one embodiment, an active agent such as a protein may be formulated in a glassy matrix of sugar which may protect the active drug from hydrolysis and prolong the preservation of the active drug. The duration and the need to chill out, for example, see Franks' title for r Long-Te rm S t ab il i zat i ο n of B iologic al sj (12 Bio/Technology 253-56 (1994)). The contents of this article are incorporated herein by reference. 22 1379682

The protein can be formulated in a glassy matrix by shifting the water in the homogenous solution of the protein. This moisture can be removed by evaporation or rapid quenching. When moisture is removed from the solution, the viscosity of the solution is such that a "solidified" liquid containing the protein is obtained. This liquid is often referred to as "glasses". Glass has a number of unique physical and chemical properties that make it an active pharmaceutical formula. Of these unique properties, the most important is that the solid retains the molecular disorder of the original liquid, which helps the glass by preventing the crystallization and reaction of the protein present in the glass. Long-term stability. Sugar re-stabilizing protein formulations also play an important role. In the liquid, the saccharide causes the denatured equilibrium reaction of the protein to proceed toward nature (n a t i v e s t a t e ). It is known that most sugars, especially low-grade carbohydrates, can be easily vitrified to provide a glassy matrix that delays the protein's reactive activity. For example, a glassy saccharide matrix useful in a system according to the present invention can be formulated and prepared by compressing together a freeze-dried mixture of protein, saccharide, buffer, and a viscous additive. Examples of egg and protein compounds in delivery systems made in accordance with the present invention include such proteins that are biologically active or useful for treating a disease or other condition. Such proteins include, but are not limited to, long hormone, VDI factor, Factor IX and its blood factors, chymotrypsin, trypsinogen, alpha-interferon ), β-galactose in addition to the dissolution to improve the "solid ideal solution. This chemistry is in the dissolution of the state of the bright light loss of choice, and the white matter treatment: bio-prothrombinase 23 1379682

(beta-galactosidase), lactate dehydrogenase, growth factors, clotting factors, enzymes, immune response stimulating factors, cytokines, lymphokines ), interferons, immunoglobulins, retroviruses, interleukins, peptides, somatostatin 'somatotropin analogues, somatic media - C (somatomedin) -C, also known as islet growth factor), gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, luteinizing hormone releasing hormone ( LHRH), LHRH analogues such as leuprolide, nafarelin and goserelin, LHRH activators and antagonists, growth hormone release factor, card Call cit on in, colchicine, gonadotropins such as chorionic gonadotropin, Oxytocin, octreotide, somatotropin plus amino acids, vasopressin, adrenocorticotrophic hormone, epidermal growth factor, prolactin Prolactin), somatotropin plus a protein, corticotropin (cosyntropin), lypressin, thyrotropin Releasing hormone), thyroid stimulation hormone, secretin, pancreozymin, enkephalin, 24 1379682 glucagons and other peptides Endocrine drugs that are endocrine and spread by blood.

Other drugs that can be used, such as α!-antitrypsin (αι-antitrypsin), 姨素, glucagon peptide, other hormones, botulinum toxin (Botox, Allergan), adrenal cortex stimulating hormone ( Adrenal cortical stimulating hormone), thyroid stimulating hormone, other pituitary hormones, interferons (eg, alpha, beta, delta interferon), erythropoietin, such as GCSFm GM -CSF and other growth factors, insulin-like growth factor-1, tissue plasminogen activator, CF4, dDAVP, tumor necrosis factor receptor, pancreatic emzyes, lactose Lactase, interleukin-1 receptor antagonist, interleukin-2's tumor suppressor proteins, cytotoxic proteins, Viruses, viral proteins, recombinant antibodies, multiple parts of antibodies and antibody fragments, and the like. And analogs, derivatives, antagonists, agonists and peptically acceptable salts of the above substances may also be used. Other active drugs encompassing the present invention include prodrugs. Prodrugs are known to enhance a variety of desirable pharmaceutical qualities, e.g., solubility, bioavailability, manufacturability, and the like. A variety of pharmaceutical dosage forms of the invention may contain a plurality of compounds in the form of prodrugs. Accordingly, the present invention also encompasses prodrugs of various active agents as claimed herein, methods of delivering such medicaments, and compositions containing §Hai music. 25 5 1379682 Analogs, such as compounds comprising a chemically modified form of a particular compound or a family of such compounds, and which are capable of maintaining the pharmaceutical and/or pharmacologically active characteristics of the compound or family, are also encompassed by the present invention. Similarly, derivatives such as chemically modified compounds are also encompassed by the present invention, wherein the modifications are common techniques that are commonly used by chemists, for example, esters or guanamines formed by acids, A protecting group for an alcohol or a thiol such as a stupid group, and a tert-butoxycarbonyl protecting group for an amine.

Various symptoms that can be treated or prevented using the above drugs include, but are not limited to, hemophilia and other blood diseases, diabetes, obesity, leukemia, hepatitis, renal failure, HIV infection, such as cerebrosidase deficiency (cerebrosidase deficiency) ) and genetic diseases such as adenine nuclear deaminase deficiency, hypertension, triumphal shock, such as multiple sclerosis, Graves di sease, systemic lupus erythematosus and rheumatoid arthritis Such as autoimmune diseases, shock and wasting diseases, cystic fibrosis, lactose insensitivity, Crohn's disease, inflammatory bowel disease, gastrointestinal cancer and other cancers, bladder management, prostate disease, pelvic cavity Abnormalities and management of uterine fibroids such as submucosal, subserosal uterine wall, parasitic fibroids and seedling myomas, such as, but not limited to, pirfenidone, Human interferin-alpha, gonadotropin-releasing hormone (GnRH) antagonist, raloxifene (R ed ο X ifene), estrogen Receptor modulators. Furthermore, fibrinogen or cytoplasmin can be introduced into a variety of formulations of the invention for the treatment of intracranial aneurysms. 26 1379682 The present invention contemplates that the LSBB topical formulations with active drugs can be applied to: contraceptives for the use of contraceptives, insulin or GLP-1; treatment for depilation or delivery of aspirin or other small molecule drugs Transdermal absorption medication; smoking cessation drugs, insulin, anti-obesity drugs, antiviral drugs (such as bubble therapy), cognac treatment drugs, hair loss treatment drugs, sore treatment drugs, erectile dysfunction drugs and anti-parasitic drugs, etc. Etc., the above are just a few examples.

The protein compound which can be used in the formulation of the present invention can be used in the form of a salt thereof, preferably a pharmaceutically acceptable salt. Useful salt forms are well known to those skilled in the art, and such salts include those formed with inorganic acids, organic acids, inorganic bases or organic bases.

The saccharides that can be used to prepare the glassy substrates previously described include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, raffinose, stachyose, maltodextrin. (maltodextrins), cyclodextrins and saccharide polymers such as dextrans and its derivatives, ficoll and temple powder. Buffers useful for formulating the glassy matrix include, but are not limited to, MES, HEPES, citrate, lactate, acetate and amino acid buffers, and the like, which are well known in the art. The LSBB system comprising a glassy sugar matrix can be comprised of a bioerodible polymer having low water permeability. Such polymers include poly(glycolic acid), poly(lactic acid), copolymers of lactic/glycolic acid, polyorthoester 27 1379682 ( Polyorthoesters), polyanhydrides, polyphosphazones, polycaprolactone. Since these polymers have low dissolution and low water absorption, they do not undergo excessive changes during the delivery of the drug.

Natural or synthetic materials suitable for use in the present invention and which are biocompatible with body fluids include, for example, polyethylene, polypropylene, polyethylene terephthalate, crosslinked polyacetate , polycarbonate, polyhard, poly(2-pentene), polymethyl methacrylate, poly(1,4-phenylene) (p〇ly(l,4-phenylene)) 'polytetrafluoroethylene and poly-ethylene-vinylacetate (EVA).

In one aspect of the invention, the adjuvant is also biodegradable or biosoluble. In the text, "bi 溶 e r 〇 d i b 1 e" and "biodegradable" are equal and can be replaced. The biodegradable adjuvant is an adjuvant which is decomposable in the body, and wherein the adjuvant must be eroded over time to achieve the drug releasing power according to the present invention. Suitable biodegradable adjuvants may include, but are not limited to, polyglycolic acid, polylactic acid, lactic acid/glycolic acid copolymers, polyorthoesters, polyanhydrides, polyphosphazones, polycarbonates. And polycaprolactone. The use of the polylactic acid _ polyglycolic acid is described in, for example, U.S. Patent No. 6,699,493, the disclosure of which is incorporated herein by reference. In another aspect of the invention, the adjuvant is biocompatible means that the adjuvant is not excessively toxic or causes a physiological or pharmacologically deleterious effect. In another aspect of the invention, the adjuvant is biodegradable. 5 28 1379682 For use in the present invention, examples of adjuvants that are biocompatible and biodegradable and/or bioerodible adjuvants can be based on the teachings of the present specification and without undue experimentation by those of ordinary skill in the art. Judging, including but not limited to:

D-tocopherol, right-handed, left-handed-α-fertility (d,1 - a -1 〇c 〇pher ο 1), right-handed -/5 - fertility (d - β -1 〇c 〇pher ο 1), right-handed, left-handed · yS - fertility (d, 1 - β -1 ocophero 1), right-handed -77 - d-rj-tocopherol, right-handed, left-handed -7?-(d,lr)-tocopherol), as well as the acetic acid 8 of the above substances, the succinic acid ester and the succinic acid-poly diol ester form, and the tocotrienols And vinegar; phenyl decyl alcohol; benzyl benzoate; dibenzoic acid diethyl ester; dibenzoic acid triethylene glycol;

Dibenzoate formed from a poly(vinyl ether) glycol having a molecular weight of about 400 mwt; propylene dibenzoate; dipropylene dibenzoate; tripropylene dibenzoate: a dimercaptoformate formed from a poly(propylene ether) glycol having a molecular weight of about 3000 mwt; a poly(acrylic acid) diol having a molecular weight of about 3000 mwt; a disulfonyl sulfone;

29 (D 1379682

Triethyl ester, tripropyl ester and tributyl ester formed from bismuth-acetonitrile citric acid; triethyl ester, tripropyl ester and tributyl ester formed from citric acid; liquid or semi-solid polycarbonate oligomerization For example, but not limited to, polymerization by trimethylene carbonate such as poly(l,3-propanediol carbonate) or diethylene Carbon k Ss (diethylene carb〇nate) with a fatty alcohol or such as poly(di-l, 2-propylene glycol carbonate) or l (1⁄2 acid-di-1) , 2-propane diester) [p〇iy(tri-l, 2-propylene glycol carbonate)], a product prepared by transesterification polymerization of polyoxyalkylene diferase. It can be used in the present invention. Examples of biodegradable/biocompatible adjuvants are “parent tocopherols (t 〇c 〇1 s).” Parent tocopherols are tocopherols and tocotrienols (t〇) C〇trjen〇is) and its derivatives 'Because tocopherols and tocotrienols are the simplest tocopherols 6-hydroxy-2-methyl- 2 -hydroxy-2-methyl- 2-phytylchroman) Derivatives. Tocopherols are known to be a family of natural or synthetic compounds known as "vitamin E." The amount of alpha fertility is abundant and is an active form in the class of this compound. Other members include: beta, gamma- and delta-tocopherol, and tocopherol derivatives such as tocopheryl acetate, succinate, nicotine, and linoleate. The tocotrienols include: dextro-<5-tocotrienol, dextro-cold-tocotrienol, dextro-o-tocotrienol and esters thereof. An adjuvant with very low viscosity, which itself 5 30 1379682 can be used not only as a carrier for drugs for injectable sustained release (IS R) formulations, but also as an additive in IRS formulations containing the above adjuvants to reduce this The viscosity of the formulation increases the near-injectability. These adjuvants include: perfluorodecalin, perfluorooctane, perfluorohexyloctane, polymethylcyclohexyloxy Courtyard (cyclomethicones In particular, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane, polydioxime with a viscosity of less than about 1000 cSt Polydimethylsiloxanes, diethyl carbonate, and dipropylcarbonate. The invention also contemplates that these liquid or solid LSBBs/active pharmaceutical formulations can be applied to the surface of the implant, such as, but not limited to, catheters, stents (cardiac, central nervous system, urinary system, etc.), artificial Fillers (eg, artificial joints, orthopedic reconstructions, and the like), tissue growth scaffolding fabrics, or bones and teeth to provide improved adhesion such as, but not limited to, anti-infective, anticoagulant, anti-inflammatory Various therapeutic properties such as force, improved tissue growth, improved biocompatibility, and the like. These surfaces may be formed from a variety of materials such as, but not limited to, natural rubber, wood, ceramics, glass 'metals, polyethylene, polypropylene, polyurethanes, polycarbonates, polyesters, polyvinyl actetates. )), polyvinyl alcohol (p〇ly (vinyl alcohols)), poly (ethylene _) (Poly (〇 xyethyienes), poly (propylene 鲢) ((P〇iy (〇 Xypr〇pyienes)), fiber Cellul〇sics, polypeptide d) 31 1379682

(polypeptides) 'polyacrylates, polymethacrylates, polycarbonate (p〇iyCarb〇nates) and the like. The active pharmaceuticals or active ingredients that can be used in the present invention without undue experimentation, including, but not limited to: analgesics, anesthetics, anesthetic analgesics, for example, acetylamino Acetaminophen; coronidine (transliteration ci〇nidine, manufacturer Duraclon Roxane) and its hydrous acid salt (commonly known as hydrochloride), sulfate and phosphate; oxycodone (oxycodene, manufacturer Percolone, Endo) and its Hydrogen acid salt, sulphate and acid salt; benzodiazepine, diazapine antagonist; flumazenil (trade name Romegiton, waste business Roche); lidocaine (lidocaine); tramadol (tramadol); carbamazepine (trade name Tegreto) Vendor; meperidine (trade name Demerol, manufacturer Sanofi-Synthelabo) and its hydrogenate, sulfate and phosphate; Zaleplon (transliteration zaleplon, trade name Sonata, manufacturer Wyeth-Ay erst); trimipramine maleate (trade name S urmonti 1 > manufacturer Wyeth-Ayer St); butyl _ (buprenorphine, trade name B uprenex, manufacturer Reckitt Benckiser); Nabufen (transliterated nalbuphine, trade name Nubain, manufacturer Endo) and its hydrochloride, sulfate and phosphate; Pantacaine (transliteration of pentazocain) and its hydrogenate, sulfate and phosphate; fentanyl and its citrate, hydrogenate, sulfate and phosphate; general 32 (f) 1379682

Propoxyphene and its hydrochloride and napsylate salts (trade name Darvocet, waste merchant Eli Lilly &Co.); hydromorphone (hydromorphone, trade name Dilaudid, trader Abbott) and Hydrogen acid salt, sulfate and acid salt; methadone (trade name Dolophine, manufacturer Roxane) and its hydrochloride, sulfate and acid salt; morphine and its hydrogenate, sulfate And phosphate; levophanol (trade name Levo-dromoran, manufacturer ICN) and its tartrate, hydrogenate, sulfate and phosphate; hydrocodone and its ditartrate, hydrogenate, Sulfate and phosphate; antagonists and / or anti-inflammatory steroids, such as: anecortive acetate (Alcon); tetrahydrocortisol-4,9 (1,1)-nivine double thin 17α,21-diol-3,20-dione (tetrahydrocortisol-4,9(l 1)-pregn adien -1 7α, 2 1 -diο 1 -3,20-diοne, manufacturer Anecortave) and its 21-acetic acid Salt; 11-epicortisol; 17a - 17α-hydroxyprogesterone; Tetrahydrocortexolone; cortisona; cortisone acetate; hydrocortisone; hydrocortisone acetate; fluorohydrogen Fludrocortisone; fludrocortisone acetate; fludroconisone phosphate; prednisone; prednisolone; pinnysolone Prednisolone sodium phosphate; methylprednisolone; thiophene serotonin acetate 33 1379682

(methylprednisolone acetate); methylprednisolone sodium succinate; triamcinolone; triamcinolone acetonide; triamcinolone-16, 21- Triamcinolone-16, 21-diacetate; propyl-trisacetin and its 21-acetate form, its -21-phosphate disodium salt form, and its -2 succinate form; Triamcinolone benetonide; triamcinolone hexacetonide; fluxinolone and fluocinolone acetate; dexamethasone and its - 21-acetate, -21-(3,3-dimercaptobutyrate),-21-phosphoric acid disodium salt -21-diethylaminoacetate,-21-isonicotine vinegar (- 21-isonicotinate), -21-dipropionate and -21-palmitate; betamethasone and its-21-acetate, -21-Yadamannoate (21-adamantoate), 1-17-benzoic acid vinegar, -17,21-dipropionic acid vinegar, -17-valerate and 21-phosphate disodium salt Beclomethasone; beclomethasone dipropionate; digasasone; diflurazon diacetate (di f) orasone diacetate; momi Mometasone furoate and acetazolamide (trade name Diamox, with multiple manufacturers); non-steroidal anti-inflammatory drugs, such as: naprosin (napr ο X i η); Diclofenac; cilec0Xib; sulindac; diflunisal (also known as diflunisal); pirosica 34 1379682

(piroxicam); indomethacin; etodolac; meloxicam; ibuprofen (ibuprofen); canopprofen (ketoprofen) R-flurbiprofen (R-flurbiprofen, manufacturer Myriad); perfenamic (mefenamic); nabumetone; tolmetin and the sodium salt of the above drugs, stroxobic acid Ke t 〇r 〇丨acbr〇methamine: ketorolac bromethamine tromethamine (trade name Acular®, waste merchant Allergan, Inc.); choline magnesium salicylate ( Choline magnesium trisalicylate); rofecoxib; valdecoxib; lumiracoxib; etoricoxib; aspirin: salicylic acid And its sodium salts; salicylates of α, r-tocopherol and tocotrienol and all their dextrorotatory, levorotatory and racemic isomers; decyl ethionylsalicylate, B Ester, propyl ester, isopropyl ester, n-butyl ester, second butyl ester and third butyl ester compound; angiogenesis Inhibitors such as squal amine, squalamine lactate (product type MSI-1256F, manufacturer Genaear) and curcumin; vascular endothelial growth factor (VEGF) inhibitors include: Tanaba (drug name pegaptanib, trade name Macugen, pharmaceutical company Eyetech/Pfizer), bevacizumab monoclonal antibody (drugizumab, trade name Avastin, drug waste Genentech/generic), shark cancer (trade name Neovastat) , Aetema); PTK 787 (Schering/Novartis), Aijiesai (trade name Angiozyme, pharmaceutical company RibozymeChiron), AZD 6474 (AstraZeneca), IMC-1C11 d) 35 1379682 (Imclone), NM-3 (ILEX Oncology ), S6668 (Sugen/Pharmacia), CEP-7055 (Cephalon) and CEP-5214 v

(Cephalon); integrin antagonists, such as Weitaxin (trade name Vitaxin, Applied Molecular Evolution/Medimmune) 'S 137 (Pharmacia), S247 (Pharmacia), ST 1646 (Sigma Tau), DPC A803350 (Bristol- Myers Squibb) and o-guanidines (o-guanudines, 3D Pharmaceutic.als/generic); matrix metalloproteinase inhibitors, such as pinomastat (scientific name prinomastat, commercial model AG 3340, pharmaceutical company

Pfizer/generic), ISV-616 (InSite Vision) ' TIMP-3 (NIH), S3304 (Shionogi), BMS 27529 1 (Ce 111ech/Bristo 1-Myers

Squibb), SC 77964 (Pharmacia), Reni Bizhuma (scientific name ranibizumab, trade name Lucentis, drug waste Genentech), ABT 518 (Abbott), CV 247 (Ivy Medical); shark cartilage extract (trade name shark cancer , pharmaceutical factory Aetema); NX-278-L-anti-VEGF suitable body

(EyeTech); 2·-0-methoxyethyl antisense C-raf oncogene inhibitor (commercial model ISIS-13650); vitronectin and osteogenic protein antagonist (3-D Pharm); combos Tantin A-4 phosphate (combretstatin A-4 phosphate, model CA4P, Oxygen Oxigene); fab fragment-α-V/β-1 integrin antagonist (Eos-200-F, Protein Design Labs); - ν/β-3 integrin antagonist (Abbott); urokinase plasminogen activator fragment (A6, Angstrom Pharm.); VEGP antagonist (AAV-PEDF, Chiron); kdr tyrosine kinase inhibitor (Model EG-3306, manufacturer Arlc Therapeutics); cytochalasin E (NIH); 36 1379682 d

Kallikrinin binding protein (Med. Univ. So. Carolina); combustatin analog (model MV-5-40, · drug seat Tulane); pigment epithelial derived growth factor (pigment-epithelium derived growth factor) > Med. Univ. SC); pigment epithelial cell-derived growth factor (AdPEDF, GenVec/Diacrin); merocytosis kringle region fragment (p 1 asmi nogen kringle, Med. Uni v. SC): rapa gutri Rapamycin); cytokine synthesis inhibitor/p38 schizophrenic activated protein kinase inhibitor (model SB-220025, manufacturer GlaxoSmithKline); vascular endothelial growth factor antagonist (model SP-(V5.2)C, manufacturer Supratek), Vascular endothelial growth factor antagonist (model SU10944, Sugen/Pfizer), vascular endothelial growth factor antagonist (model VEGF-R > pharmaceutical Johnson & Johnson/Celltech), vascular endothelial growth factor antagonist (VEGF-TRAP, Regenron, FGF1 Receptor Antagonist / Luciferase Kinase Inhibitor (Pfizer/Sugen), Endostatin, Vascular Endothelial Growth Factor Antagonist (EntreMed), Bradykinin B1 receptor antagonist (model B-9858, manufacturer Cortech), bactericidal/permeability enhancing protein (abbreviated BPI, manufacturer Xoma), protein kinase C inhibitor (trade name) Hypericin, pharmaceutical company Kansai Med. U,), ruboxistaurin mesylate (model LY-3 3 3 53 1, pharmaceutical company Eli Lilly & Co.), polysulphonic acid derivative (polysulphonic acid) Fins, Fuji Photo Film), growth factor antagonist (model TBC-2653, TB C - 3 6 8 5 > manufacturer Texas Biotechnology), Tonici endothelial cell kinase (Tunica internal endothelial cell kinase) ) 37 1379682

Amgen); anti-infective agents, such as antibacterial agents including aztreonam; cefotetan and its sodium salt; loracarbef; cefoxitin and its sodium salts; Cefazo丨in and its sodium salt: cefacor; ceftibuten and its salt; head cuddle (ceftizoxime); head hug. Sitting on the salt of the fat; the head holding the oxygen mother stupid. Cefoperazone and its sodium salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil; head ceftazidime; Head cefotaxime and its sodium salt; head cuddling with cefadroxil; head holding him bite and its salt; cephalexin; head cefamandole nafate; head hug (cefepime) and its hydrochloride, sulphate or phosphate; cefdinir and its sodium salt; ceftrixone and its sodium salt; cefixime and its sodium salt; Cefpodoxime proxetil; meropenem and its sodium salt; imipenem and its sodium salt; cilastatin and its sodium salt; azithromycin Clarithromycin (or clarithromycin); didirthromycin; erythromycin and its hydrochloride, sulfate or acid; ethyl succinic acid Ethylsuccinate) and its stearate form; clindamycin; clindamycin hydrochloride, sulfur Acid or sulphate; lincomycin and its hydrochloride, sulphate or sulphate; tobramycin and its hydrochloride, sulphate or sulphate; streptomycin (streptomycin) and its hydrochloride, sulfate or acid 38 (I) 1379682

Salt; vancomycin and its hydrochloride, sulfate or dish acid salt; neomycin and its hydrochloride, sulfate or 4 acid salt; acetyl sulfis 〇xaz〇le); polymyxin E (colistimethate) and its sodium salt; quinupristin: dalfopristin; amoxicillin; And its sodium salt; clavulanic acid and its sodium or bell salt; penicillin G; penicillin G benzathine or its procaine salt ); sodium or strontium salt of chlorinated G; carbenicillin and its di-nano salt or its diarsenyl di-nano salt; ° piperacillin and its sodium salt; ticarcillin ( Ticariclin) and its di-salt salt; sulbactam and its sodium salt: moxifloxacin; sepfenshacin; ofofoxacin; levofloxacin (丨evofloxaci ns ); norfloxacin; gatifloxacin; trofasarsin acid (salt) (trovafloxac) In mesylate); alatrofloxacin mesylate; trimethoprim bite (or trimethoprim bite. 'trimethoprim); reductive amine. Sulfamethoxazole; dephosphomycin (or dimethocycline, demeclocycline and its hydrochloride, sulphate or sulphate; deoxycycline and its hydrochloride, sulphate or Phosphate; minocycline and its hydrochloride, sulfate or phosphate; tetracycline and its hydrochloride, sulfate or phosphate; oxytetracycline and its salts Acid salt, sulfate or phosphate; gas tetracycline (chlortetracycline) and its hydrochloride 'sulfate or phosphate; fnitrozolidine (metronidazole); rifampin; 39 1379682 Dapsone, or aminobenzoquinone); atovaquone; rifabutin (chemical name 4-N-isobutylspiropiperidin rifamycin s); linezolide; multiple sign B (polymyxin B, or polymyxin b) ί and its hydrochloride, sulfate or phosphate; sulfacetamide and its sodium salt; minocycline; and clarithromycin;

Anti-altery agents, such as amphotericin B (amphoterici η B); pyrimeth amine; flucytosine; caspofungin acetate; fluconva; Griseofulvin; terbinafin and its hydrochloride, sulfate or acid salt; ketoconazole; micron azole; Chromrimazole; econazole; ciclopirox; naftifine; and itracon. Sitting (itraconazole);

Antimalarial drugs, such as chloroquine and its hydrochloride, sulfate or disc acid salt; hydroxy quinine (hydr〇xychl〇r〇quine) and its hydrochloride, sulfate or sulphate; Mefiquinine (mefi〇quine) and its hydrochloride, sulphate or sulphate; atorvavir (a 10 V aqu ο ne ); proguanil and its hydrochloride, sulphate Or an acid-filled form; an anti-tuberculosis agent, such as ethambutol (ethambut ο 1) and its hydrochloride, sulfate or phosphate form; aminosalicylic acid, isoniazid , pyrazine, pyrethinamide, ethyl bowl of ethionamide; antiviral agents, such as amprenavir (amprenavir), interferon alpha-n3 (interferon alfa-n3), interferon a -2b (interferon alfa-2b), complex 40 1379682 interference (interferon alfacon-l), polyethylated interferon alpha-2b (peginterferon alfa-2b), interferon a _2a (interferon

A

Alfa-2a), lamivudine, zidovudine, omandine (scientific name amadine 'seller name Symmetrel 'vendor Endo) and its hydrochloride, sulfate or phosphate; indinavir (indinavir, trade name: gram full) and its hydrochloride, sulfate or phosphate; ganciclovir; ganciclovir sodium; famciclovir; amantadine (or turtle) Rhamantadine and its hydrochloride, sulfate or acid salt; saquinavir mesylate; foscamet,

Zacitabine, ritonavir; ribavirin; zanamivir; delavirdine mesylate; efavirenz Amantadine and its hydrochloride, sulfate or acid salt; pali vizumab, oseitami vir and its hydrochloride, sulfate or phosphate; Abacavir and its hydrochloride, sulphate or phosphate; valganciclovir and its hydrochloride, sulphate or phosphate; val acyclovir and its Hydrochloride, sulphate or phosphate; didanosine; nelfinavir mesylate; nevirapine; sidofus; acrocolo; Trifluridine; penciclovir 'zinc oxide; zinc salicylate; all tocopherylsuccinic acid isomers zinc salt; c2-C2〇 linear , branched chain, zinc salt of saturated and unsaturated fatty acids; zinc pyruvate' lactic acid (zinc iactate); zinc vinegar complex (zinc 41 (§) 1379682 ester complexes), and zinc acetoacetonate. or zinc acetoacetic ester complexes; Immune Deficiency Syndrome (AIDS/HIV/A IDS) agents, including stavudine 'reverset (Pharmasset)'

Product model ACH-126443 (pharmaceutical Achillion), product model MIV-310 (pharmaceutical company Boehringer Ingelheim), Zilit IR (trade name ZeritIR (d4tT), medicine cheap Bristol-Meyers Squibb), Ji Gang (trade name Ziagen, Pharmaceutical company GlaxoSmithKline), Virida (trade name Viread, pharmaceutical company Glead), diafiltration (trade name hivid, pharmaceutical company Roche), Ancuiwa (trade name Emtriva, pharmaceutical company Gilead), delavirdine (drug waste) Pfizer), AG-1549 (Pfizer), DPC-083 (Bristol-Myers Squibb), NSC-67545 1 (Advanced Life Sciences), IMC-125 (Tibitec), Azo Amin (azidicarbonamide), GPG-NH2 (pharmaceutical Tripep), immunization (drug name iminunitin, drug waste Colthurst), cell spirit (trade name cytolin, pharmaceutical company Cytodyn), HRG-214 (pharmaceutical company Virionyx), MDX-010 (pharmaceutical Gilead), TXU-PAP (pharmaceutical company Wayne Hughes Inst), Prius (trade name proleukin, pharmaceutical company Chiron), BAY 50-4798 (pharmaceutical Bayer), G-777 (medicine rot; Virocell), Gram filter (trade name Crixivan, pharmaceutical company Merck), Fuai (trade name Fuzeon, pharmaceutical factory Hoff-La Roc He), WF-10 (Pharmaceutical Oxo Chemie) 'Ad5 Gag vaccine (pharmaceutical Merck), APL400-003 and 047 (pharmaceutical Wyeth), Remunin (trade name)

Remunex, pharmaceutical company Immune Response Corp.), product model (!) 42 1379682 MVA-BN Nef (Pharmaceutical waste Bavarian Nordic), GTU MultyHTV vaccine (pharmaceutical FIT Biotech);

Insulin, such as the products of Novo Nordisk: 甘精错沃洛 (1^0^〇丨〇名38?31^), Novoline ruler (1^〇乂〇1) ), Novolin N, Novolin L, Novolin 70/30 and Novolo 70/30; and Eli Lilly from the pharmaceutical company: Humalog lispro ), Humulin R, Humulin N, Humulin L, Schumarin 50/50 and 70/30, and Humalog Mix 75 /25 and 70/30; ultra long-acting insulin (trade name Ultratele, pharmaceutical company Eli Lilly); Rantes (trade name Lantus glargine, medicinal Aventis); porcine sulphate; and bovine insulin;

Glucagon-like peptide-1 (Gipl) and its analogues (for the treatment of diabetes, appetite suppression and cardiovascular protection) (see Keiffer et al., 20 Endocr Rev., 876-913 (1999); Gipl receptor Stimulating factors, such as exendin-4, Exenatide and exenatide LAR (Amylin Pharma); liracopeptide (trade name Liraglutide, pharmaceutical company Novo Nordisk); ZP -10 (Zealnad Pharma); Glp-1-albumin (Glp-1-albumin, pharmaceutical company Conjuchem); and Dpp-IV inhibitor (which inhibits the enzyme that attacks Glp-1), such as LAF237 (Novartis), MK- 043 1 (Merck), BMS-477 1 88 (Bristol-Myers Squibb) and GSK23A (GlaxoSmithKline); alpha-type male agonist, such as brimonidine tartrate; beta-adrenergic blocker , for example, beta 43 1379682, betaxolol and its hydrochloride, sulfate or phosphate; levobetaxolol and its hydrochloride, sulfate or phosphate; and dimero maleic acid Ester (timolol maleate); % carbonic anhydrase inhibitors such as brinzolamide; more left An amine (dorzolamide) and its hydrochloride, sulfate or phosphate; and dichlorphenamid;

Mast cell stabilizers such as pemirolast and its potassium salts; nedocromil and its sodium salts; cromo丨yn and its sodium salts; a cholesterol ester inhibitor), such as demecarium bromide; a prostaglandin such as bimatoprost, travoprost, and iatanoprost;

An antihistamine such as olopatadine and its hydrochloride, sulphate or sulphate form; fexofenadine and its hydrochloride, sulphate or phosphate form; A.ze las tine and its hydrochloride, sulphate or phosphate form; diphenhydramine and its hydrochloride, sulphate or phosphate form; promethazine 01'〇11161» 13 2丨1^) and its hydrochloride, sulfate or phosphate form; anti-microtubules, such as cedar, including paclitaxel (scientific name paclitaxel, trade name Taxol, drug barrier Bristol-Myers Squibb); Changchun New Alkali (trade name Oncovin, Eli Lilly & Co.) and its hydrochloride, sulfate or citrate form, · Changchun (scientific name vinblastine, trade name Velbe, pharmaceutical company Eli Lilly & Co.) and its salts Acid salt, sulfate or phosphoric acid 44 1379682

Salt; vinblastine (scientific name vinorelbine, trade name Novelbinr, drug waste Fabre/GSK); colchicine; European paclitaxel (scientific name docetaxel, trade name Taxotere, drug waste Aventis); 109881 (Aventis); LIT 9 7 6 (Aventis BMS 1 8 8 7 9 7 (Bristol-Myers Squibb) ; BMS 1 84476 (Bristol-Myers Squibb); DJ 927 (Daiichi); DHA-paclitaxel (DHA paclitaxel, trade name Taxoprexin, Protarga) Epothilones, including: Epothilone B (EPO 906, Novarti s/generic); B MS 247550 (Bristol-Myers Squibb); BMS 310705 (Bristol-Myers Squibb); Epothilone D (KOS) 862, Kosan/generic); and ZK EPO (Schering AG);

Antineoplastic agents, for example: doxorubicin and its hydrochloride, sulfate or phosphate; idarubicin and its hydrochloride, sulfate or phosphate; torinoise (transliteration) Daunorubicin) and its hydrochloride, sulfate or acid salt; dactinomycin: epirubicin and its hydrochloride, sulfate or phosphate; dacarbazine Paccamycin; mitoxantrone (scientific name mitoxantrone > trade name Novantrone, pharmaceutical plant OSI Pharmaceuticals) and its hydrochloride, sulfate or phosphate; valrubicin (Cytarabine); Niluta (transliteration nilutamide), Bikarutamai (transliteration bicalutamide); Fotamai (fluentamide), Anato. Sitting (anastr〇z〇ie); exemestane (exemestane), toremifene (transliteration t〇remifene); femana (transliteration femara), tamoxifen (transliteration tam〇xifen) and tamo Cifen citrate; 45 1379682%

Temozolomide (scientific name temozolimide, Temador); gemsitabin (transliterated gemcitabine) and its hydrochloride, sulphate or phosphate; topotecan and its hydrochloride, sulfate or phosphate; vincristine and Its hydrochloride, sulfate or phosphate; vesicular vincristine (One o-TCS, Inex/Elan); methotrexate and methotrexate sodium salt; cyclophosphamide; Estramustine sodium phosphate; Leprole and Leprox acetate; Goserelin (goserelin and goserelin acetate; estradiol: Ethynyl estradiol; Menest esterified estrogens; Premarin conjugated estrogens; 5-fluorourine shouting. (5-flurouracil); bortezamib (drug name bortezamib, trade name Velcade, pharmaceutical company Millenium Pharmaceuticals); anti-apoptotic agents, such as demethylpropargylamine (drug name desmethyldeprenyl, DES, pharmaceutical company RetinaPharma) ;

Aldose reductase inhibitors such as GP-1447 (Grelan), NZ-314 (parabanic acid derivative, Nippon Zoki), SG-210 (Mitsubishi Pharma/Senju) and SJA-7059 (Senju); antihypertensive agents, for example : Candesartan g (scientific name candesartan cilexetil, trade name Atacand/Biopress, pharmaceutical company Takeda/AstraZeneca/Abbott), Losartan (scientific name lostartan, pharmaceutical company Cozaar, Merck) and Lishinop (scientific name lisinopril, goods Zestril/Prinivil, pharmacy Merck/AstraZeneca); antioxidants such as phenyl thiamine (scientific name benf 〇tiamine, pharmaceutical factory 46 1379682

Albert Einstein Col. Of Med./WorWag Pharma), ascorbic acid and its esters, tocopherol isomers and their esters; and rossostat (scientific name r ax of e 1 as t, model IRFI- 00 5, Pharmacy B i 〇medi ca Foscama); growth hormone antagonists, such as somatostatin peptide (trade name Sandostatin » Yaolian Novartis) and acromegaly therapeutic agent (scientific name pegvisomant, trade name Somavert &gt ; drug waste Pfizer / Genentech);

Vitreous resection agents, such as hyaluronidase (scientific name hyaluronidase, trade name Vitrate, ISTAPharm, / Allergan); adenine nucleoside receptor antagonists, such as A2B adenine nucleoside receptor antagonist (754, Adenosine Therapeutics) ; adenine nucleoside deaminase inhibitors, such as Pantostatin (scientific name pentostatin, trade name Nipent, medicine Wei Supergen); auditory antagonists, for example, 0 to guanamine (scientific name pyridox + amine, trade name Pyridorin, pharmaceutical company Biostratum);

Anti-aging peptides, such as Ala-Glu-Asp-Gly (trade name Epitalon, pharmaceutical company St Petersburg Inst. Bioreg. and Geron); topoisomerase inhibitors, for example: doxorubicin (trade name Adriamycin/Caelyx) , pharmaceutical company Phannacia/generics), Taunobis (or daunorubicin, trade name DaunoXome, pharmaceutical Gilead/generics), etoricin (scientific name etoposide, trade name Vepecid/Etopophos, pharmaceutical company Bri stο 1 - Myers Squibb/generics), Idarubicin (Idamycin, trade name Idamycin, pharmaceutical Pharmacia)' Irinotic (scientific name irinotecan, trade name Camptosar, Pharmacy 47 1379682

Pharmaci a), Topotecan (trade name: Hycamtin, GlaxoSmithKline), Pan-Ai (Syllabus Ellence, Phamacia) and Retitrexed (scientific name raltitrexed, trade name Tomudex, AstraZeneca) ;

Antimetabolites such as amidoxime (generic) and its sodium salt, 5-fluorourine bite (trade name Adrucil, medicinal rot; ICN Pharmacia), Saida (scientific name c ytarabine) trade name Cytosar > Pharmacia/generic), fludarabine (scientific name fludarabine, trade name Fludara, pharmaceutical company Schering) and its salts with acid, Jessitabin (trade name Gemsar, pharmaceutical company Eli Lilly & Co·), tumor (capacitabine, trade name Xeloda, pharmaceutical company R〇che), and perillyl alcohol (ΡΟΗ, pharmaceutical company Endorex);

A rejuvenating agent such as chlorambucil (ch 1 orambuci 1, trade name Leukeran, pharmaceutical company GlaxoSmithKline), cyclophosphamide (trade name Cytoxan' Pharmacia/Bristol-Meyers Squibb), gastrolesin (transliteration) Methchlorethanine, pharmaceutical generic), 顺# (scientific name cisplatin 'trade name piatinal, pharmaceutical company Phannacia/Bristol-Meyers Squibb), card start (scientific name carboplatin, trade name Paraplatin, pharmaceutical company Bristol-Myers Squibb), timozhuluoming (sound class temozolominde, Temodar) and diamine ring hexaxy oxalic acid surface (scientific name oxaliplatin, pharmaceutical factory

Sanofi-Synthelabs); anti-androgenic agents' such as Fotame (trade name E u 1 e X i η, pharmaceutical factory)

AstraZeneca), Nilitamai (trade name Anandron, pharmaceutical company Aventis), Pikaruta (trade name: Caodex, pharmaceutical company AstraZeneca); 48 1379682 Anti-estrogen agent, such as Tamoxifene (trade name Nolvadex, medicine) Plant AstraZeneca), Torremolino (scientific name tore mof ine, trade name Fareston's medicinal Orion/Shire), Farod (trade name Faslodex, pharmaceutical company AstraZeneca), azociline (scientific name arzoxifene, pharmaceutical company Eli

Lilly & Co.), Alibide (trade name Arimidex, pharmaceutical company AstraZeneca), letrozole (trade name letrozole, trade name Femera, pharmaceutical company Novartis), lantalon (trade name Lentaron, drug waste Novartis),

Norman cancer (trade name Aromasin, pharmaceutical company Pharmacia), Farrell (trade name Zoladex, pharmaceutical company AstraZeneca), lansofene (transliteration lasoxifene, model CP-366, 156, pharmaceutical company Pfizer), ERA-923 (Li Gand/Wyeth) , DCP 9 7 4 (DuPont/Bristol Myers

Squibb), ZK 235253 (Shering AG), ZK191 1703 (Shering AG) and ZK 23021 l (SheringAG);

Inhibitors of oncogene activation, including, for example, Bcr-AbI kinase inhibitors, such as kilik (trade name Gleevec, pharmaceutical company Novartis); Her2 inhibitors, such as trastuzumab anti-barrel (drug name trastuzumab, trade name He. Rceptin, Genentech), MDX 210 (Medarex), E1A (Targeted Genetics), ME 10 3 (Pharmexa), 2C4 (Genentech) 'Cl-1033 (Pfizer), PK1 166 (Novartis), GW572016 (GlaxoSmithKline) and ME104 (Pharmexa); EGFr inhibitors, such as Erbitux (trade name Erbitux, pharmaceutical company Im c 1 〇ne/B ri st ο 1 - M y ers Squibb/Merck KgaA); EGFr tyrosine kinase inhibitors, such as Kyrgyzstan Fentinib (drug name gefitinib, trade name Iressa ZD 1 839, pharmaceutical company AstraZeneca), cetuximab antibody (drug name 49 1379682)

Cetuximab, trade name Erbitux, medicine court Imclone/BMS/Merck KGaA), erlotinib (drug name erlotinib, trade name Tarceva, medicine court OSI PharmaceuticaVGenentech/Roche), ABX-EGF #

(Abgenix), Cl-1033 (Pfizer), EMD 72000 (Merck KgaA), GW572016 (GlaxoSmithKline), EKB 569 (Wyeth), PKI 166 (Novartis) and BIBX 13 82 (Boehringer Ingleheim); farnesyltransferase inhibitors (famesyl Transferase Inhibitors), such as tifenbini (drug name tipifarnib, trade name Zamestra, medicine Wei Johnson & Johnson), ronfani (drug name lonafarnib, trade name Sarasar, medicinal Schering-Plough), BMS- 214,662 (Bristol-Myers

Squibb), AZ3409 (AstraZeneca), CP-609, 754 (OSI

Pharmaceutical s), CP-663, 427 (OSI

Pharmaceutical s/Pfizer), Arglabin (NuOncology), RPR-13040 1 (Aventis), A 176120 (Abbott), BIM 46228 (Biomeasure), LB 42708 (LG Chem), LB 42909 (LG Chem), PD 169451 (Pfizer) And SCH226374 (Schering-Plough); Bcl-2 inhibitors, such as BC: LX (Isis), ODN 2009 (Novartis), GX 011 (Gemin X) and TAS 301 (Taiho); Cyclin-dependent kinase inhibitors (Cyclin) Dependent Kinase Inhibitors), such as flavonoids 0 than alcohol (drug flavopiridol, pharmaceutical generic, Aventis), CYC202 (Cyciacel) 'BMS 387032 (Bristol-Myers Squibb) ' BMS 23 9091 (Bristol-Myers Squibb), BMS 250904 (Bristol -Myers Squibb), CGP 79807 (Novartis), NP102 (Nicholas Piramal) and NU 6102 50 1379682 9 (AstraZeneca); protein kinase C inhibitors, such as Affinita (trade name Affinitac, pharmaceutical company Isis, Eli Lilly & Co.), domostatin (drug name midostaurin, product model PKC 412, drug waste Novartis/generic), macrolide bryostatin (scientific name bryostatin, pharmaceutical company NCI/GPC Biotech/generic), KW 2401 ( NCI/Kyowa Hakko), LY 317615 (E Li Lilly & Co.), Pelifferin (scientific name perifo sine, pharmaceutical company ASTA Medica/Baxter/generic) and SPC 100840 (Sphin x);

Telomerase inhibitors such as CRN 163 (Geron/Kyowa Hakko) and G4T 405 (Aventis);

Antibody therapeutics, including Herceptin (trade name Herceptin, pharmaceutical company Genentech/Roche), MDX-H210 (Medarex), SGN-15 (Seattle Genetics), HI 1 (Viventia), Cyrus (trade name The rex, Drugstore Antisoma), Litrichman (transliteration rituximan, trade name Rituxan, drug genus Genentech), Campas (trade name Campath, pharmaceutical company ILEX Oncology/Millennium/Shering), medullary tumor (trade name Mylotarg, pharmaceutical factory Celltech/Wyeth) 'Zevain (trade name Zevalin, pharmaceutical company IDEC Pharmaceutical s/Schering), Tosimo single anti-Zhao (scientific name tositumomab, trade name Bexxar, medicine core Corixa/SmithKline Beecham/Coulter), Yibazhu Monoclonal antibody (scientific name epratuzumab, trade name Lymphocide, pharmaceutical company Immunomedics/Amgen), O'Connor (trade name Oncolym, pharmaceutical company Techniclone/Schering AG), Mab Hu I DIO antibody (Protein Design Laboratories), ABX-EGF (Abgenix) Infliximab antibody (scientific name infliximab, trade name Remicade®, pharmaceutical company Centocor) and, Itanasi (scientific name 51 1379682 etanercept, trade name Enbrel, drug waste Wyeth-A Yerst); antisense oligonucleotides, such as Affinita (Isis Pharmaceuticals/Eli Lilly & Co.) and Gennas (trade name Genasence, pharmaceutical company Genta/Aventis); fusion proteins such as diphtheria Toxin-mediated interleukin 2 fusion protein (denileukin diftitox, trade name Ontak, drug waste Ligand);

Luteinizing hormone-releasing hormone (LHRH) agonist and gonadotropin-releasing hormone (GnRH) agonist, such as goserelin (trade name Zoladex, drug waste AstraZeneca), leuprolin (transliteration 丨Euporelin, trade name Lupron, pharmaceutical company Abbott/Takeda), Replin acetate acetate (trade name Viadur, pharmaceutical company ALZA/Bayer, Atigrel/Eligard, Atrix/Sanofi-Synthelabo) and Triptorel (scientific name triptorelin, trade name Trelstar, pharmaceutical company Pharmaceuticals);

Tyrosine kinase inhibitor/EGFR inhibitors, such as gefitinib (Iressa, AstraZeneca, ZD 1 83 9), trastuzumab antibody (trade name Herceptin, pharmaceutical company Genentech), erlotidine Nie (trade name Tarceva, medicinal waste 〇 SI Phan. maceuticals, model OSI 774), cetuximab antibody (trade name Erbitux, pharmaceutical company Imclone Systems, model IMC 225) and patezum monobe antibody (scientific name pertuzumab, Trade name Omnitarg, pharmaceutical company Genentech, model 2C4); ribonucleoside reductase inhibitors, such as gallium maltate (gallium maltolate, pharmaceutical plant Titan); cytotoxins, such as elfofen (trade name Irofulven, commodity Model MGI 114, pharmaceutical company MGI Pharma); 52 (f) 1379682

Interleukin-2 therapeutic agents, such as rifampin (trade name Leuvectin, pharmaceutical Vical); neurotensin antagonists, such as SR 48692 (Sanofi-Synthelabo); peripheral sigma-ligands, such as SR 3 1 747 (Sanofi-Synthelabo); Endothelin ETA/receptor antagonists, such as YM-598 (Yamanouchi) and atrasentan (drug name atrasentan, model ABT-627, manufacturer Abbott); hypoglycemic agents, such as metformin (drug name) Metfonnin, trade name Glucophage, Bristol-Myers Squibb) and its hydrochloride, sulfate, phosphate; and miglitol (drug name miglitol, trade name Glyset, pharmaceutical Pharmacia/Upjohn); anti-glaucoma agent, for example Letromine (trade name Cosopt, Merck); Dimethoate; Betaxullo and its hydrochloride, sulfate, phosphate; Atinolo; and Koloshali (transliteration c 1 〇rtha 1 id ο ne); an anti-(chromosome-modified enzyme) agent, such as cycloheptyl anilide hetero-hydroxy acid (a drug name suberoylanilide hyroxamic acid, pharmaceutical Aton/Merck); an obesity management agent such as a glyphosate-like peptide; Fentamicin (transliteration phendimettr.azine) Its tartrate, hydrochloride, sulfate, phosphate; methamphetamine and its hydrochloride, sulfate, sulphate, and sibutramine (named sibutramine, trade name Meridia, pharmaceutical company Abbott) ) and its hydrochloride, sulfate, phosphate; anemia therapeutics such as erythropoietin alpha (trade name Ε ρ 〇ge η, pharmaceutical Amgen), erythropoietin alpha (trade name Eprex/Procrit, medicine 53 ( S) 1379682 -^

Waste Johnson & Johnson), erythropoietin a (ESPO, medicinal waste Sankyo & Kirin) and darbepoetin alpha (trade name Aranesp, pharmaceutical company Amgen), erythropoietin (trade name) NeoRecormon, Roche), erythropoietin cold (trade name Epogen 'pharmaceutical Chugai), GA-EPO (trade name Dynepo, drug waste TKT/Aventis), erythropoietin 7 (Elanex/Baxter), R 744 (Roche ) and erythropoietin (thrombopoetin, pharmaceutical company Genetech/Pharmacia) i ° area vomiting therapeutic agents, such as isopropyl hydrazine (trade name P henerga η, pharmaceutical company Wyeth), propionate chlorene (prochlorperazine), methyl oxygen Putamine (scientific name metoclopramide, trade name Reglan, pharmaceutical company Wyeth), fluorine "droperidol", fluorine haloperidol, dronabinol (Roxane) 'Ou Danxi frustration (scientific name ondansetron, Trade name Zofran, drug waste GlaxoSmithKline), Gangi West setback (scientific name ganisetron, trade name Kytril, pharmaceutical company Roche), Dora West set (scientific name

Dolasetron, trade name Anzemet, Aventis) 'India dynasty (scientific name: INDisetron, model NN-33 89, pharmaceutical company Nisshin Flour/Kyorin), Alibiptan (scientific name aprepi tant, model MK-8 69, manufacturer Merck), Baron West Frustration (scientific name palonosetron, pharmaceutical company Roche/Helsinn/MGI

Pharma), lerisetron (FAES), benzene continuation (not known as nolpitantium' model SR 14033, manufacturer Sanofi-Synthelabo), R1 124 (Roche), VML 670 (trade name Vemalis, pharmaceutical company Eli Lilly & Co.) and CP 122721 (Pfizer); therapeutic agents for neutropenic hypoxia, such as filgrastim (drug name 54 1379682 filgrastim, trade name Neupogen, Weismann Amgen), lukein (trade name leukine, "Immunex/Schering AG", PEGylated filgrastim (drug name filgrastim-PEG, trade name Neulasta, waste Amgen), PT 100 (Point Therapeutics) and SB 25 1 353 (GlaxoSmithKline);

Tumor-induced hypercalcemia therapeutic agents, such as bone vitamins (trade name Bonviva, pharmaceutical factory (GlaxoSmithKline), Ibandronate (scientific name ibandronate » trade name Bondronat, pharmaceutical company Roche), Pamidinate (scientific name) Pamidronate, trade name Aredia, pharmaceutical company Novartis), levophosphonate (scientific name zolendronate, trade name Zometa, pharmaceutical company Novartis), clodronate (scientific name clodronate, trade name Bonefos, pharmaceutical gene), card scale Acid salt (scientific name incadronate, trade name Bisphonal, medicine Wei Yamanouchi), drusen (scientific name calitonin > trade name Miacalcitonon, pharmaceutical plant Novartis), minoxidin (scientific name minodronate, model YM 529/Ono 5 9 20 , Medicine

Yamanouchi/Ono) and anti-PTHrP (CAL, Chugai);

Anticoagulants, such as Agathroban (GlaxoSmithKline); Warfarin (trade name Coumadin, duPont); heparin (trade name Fragmin, Pharmacia/Upjohn) Hepatic thioester (pharmaceutical Wyeth-Ayerst); Tirofiban (transliterated tirofiban, trade name Aggrastat, pharmaceutical company Merck) and its hydrochloride, sulfate, acid salt; double-dipamine (scientific name dipyridamole, Trade name Aggrenox, pharmaceutical company Boehringer Ingelheim); Anagre (scientific name anagrelide, commodity 5 55 1379682

A grylin, pharmaceutical company Shire US) and its hydrochloride, sulfate, phosphate; epoprostenol (scientific name epoprostenol, trade name Flolan, drug waste GlaxoSmithKline) and its hydrochloride, sulfate, phosphate; Non-peptidide (scientific name eptifibatide, trade name Integrilin, drug The COR Therapeutics); (scientific name clopidogrel, trade name Plavix, Bristol-Myers Squibb) and its hydrochloride, sulfate or acid salt; cilostazol ( Scientific name cilostazol, trade name Pletal, pharmaceutical company Pharmacia/Upjohn); acixin (abciximab, trade name Reopro, pharmaceutical company Eli Lilly & Co.) and thiazide (scientific name ticlopidine, trade name Ticlid, drug waste Roche) Immunosuppressive agents such as sirolimus (rapamycin, trade name Rapamune® 'Wyeth-Ayerst Pharmaceuticals), Tacomomos (trade name Prograf, model FK506) and cyclosporine; tissue repair agents , for example, Chrysallin (model TRAP-508, manufacturer Orthologic-Chrysalis Biotechnology);

Anti-drying agents, such as anthra丨i η, vitamin D 3, cyclofamily, methotrexate, etretinate, salicylic acid, isotretinoin and sebum Corticosteroids; anti-acne agents such as retinoic acid or A acid, benzoyl peroxide, sulfur-resorcinol, azelaic acid , clendamycin, erythromycin, myopic acid, tetracycline, minocycline; anti-skin parasites, such as permethrin and benzo B $) 56 1379682

°S saliva (thiabendazole); therapeutic agents for hair loss, such as minoxidil and finasteride; contraceptives, such as medroxyprogesterone, norltim ( Norgestimol), desogestrel (or desogestrel, desogestrel), levonorgestrel, norethindrone, ethynodiol and acetylene A quit smoking therapeutic agent, including acid testing (or nicotine, nicotine, bupropion, and buspirone; erectile dysfunction therapeutics, such as prostaglandin E 1 (a 1 prostadi) 1) with dexnaufil (Sildenafil, trade name, Will Gang); DNA-alkyltranferase activators, including temozolomide; metalloproteinase inhibitors, for example Marimastat; drugs that control wrinkles, bladder, prostate and pelvic abnormalities, such as botulinum toxin; uterine fibroids control agents such as piperphenidone, alpha-human interferon, gonadotropin release GnRH antagonist, raloxifene, estrogen receptor modulator; transferrin activator, including TransMID (Xenova Biomedix) and Tf-CRMl〇7 (KS Biomedix); interleukin-13 Bulk agonists, such as IL-13-PE38QQR (Neoph arm); Nucleic acids, such as small interfering RNAs (siRNA) or RNA interferences 57 1379682

(RNAi), in particular, for example, siRNAs that interfere with the expression of VEGF; and psychotherapeutic agents include: anxiolytics such as chlordiazepoxide, diazepam, chlorazepate, fluoxetine (flurazepam), halazepam (halazepam), praxipam (prazepam), clorazepam, quarzepam, apuron ( Alprazolam), lorazepam, orazepam, temazepam (via diazepine or carbazide, temazepam) and three. Tri azol am; and antipsychotic drugs, such as aerobic. Chlorpromazine; thioridazine, mesodar "mesoridazine, —trifluorperazine, fluphenazine, loxapine, mazin Ketone (molindone), methionine (or thiothixene), fluocinol (trade name: harperin dol, haloperi dol), pimozide and clozapine 〇 the field It will be apparent to those skilled in the art that any of the above active agents may be used in combination or in combination in the pharmaceutical formulations of the present invention. These mixtures or compositions can be delivered in a single formulation or as different formulations administered at the same time or at different time points to achieve the desired therapeutic result. In addition, many of the above drugs may have more than one activity or have more than one therapeutic use and should not be limited to the specific ranges described herein. Likewise, various biodegradable, biocompatible adjuvants can be used in compositions or mixtures in single or multiple formulations, if desired. Those skilled in the art can determine according to the disclosure herein without undue experimentation. 5 58 1379682 4.

Mixtures and compositions of these active agents with adjuvants. The various formulations of the present invention can be sterilized using conventional methods. Steam sterilization and electron beam sterilization methods can be used in a simplified experiment of several embodiments without significant impact. Similarly, a brief stability study shows that several embodiments have acceptable stability. In addition, the reproducibility between the small package and the batch is good, and the standard deviation is less than 5% or better. Therefore, standard pharmaceutical technology can be applied immediately to the techniques described herein. An embodiment of the present invention comprises the active drug "dexamethasone" and the adjuvant "benzyl benzoate". Dexamethasone is a glucocorticoid and is usually used in the form of its acetic acid vinegar or disodium phosphate ester. Glucocorticol is a corticosteroid that inhibits the inflammatory response caused by various mechanical, chemical or immunological factors. Dexamethasone can be administered by topical, upper eye, systemic (oral) and vitreous injection. The dosage is changed according to the condition of the patient to be treated and the individual's reaction. Since the introduction of a 0.1% solution of dexamethasone phosphate sodium salt (Decadron® Merck & Co.) in 1957, it has been widely used in the field of ophthalmology. The amount of the ophthalmic dose depends on the condition to be treated. In order to control the inflammatory response of the anterior chamber of the eye, the amount of topical medication after surgery is usually 4 times per dose, one drop at a time, for 1 month (about 5 mg per ounce). If you want to control the inflammatory response in the posterior segment of the eye, 4 mg of dexamethasone is usually injected into the eyeball, or 0.75 mg to 9 mg of dexamethasone is administered orally daily. Intravitreal injection of 0.4 mg of dexamethasone can be combined with antibiotics to treat endophthalmitis. (S) 59 1379682

Benzyl benzoate (CAS 120-51-4, FW 212.3). In the past, it was claimed that oral administration of benzyl benzoate was effective in the treatment of intestinal, bronchial and bladder diseases, but its use has been replaced by more effective drugs. Recently, benzyl benzoate has been used as a topical drug for the treatment of sputum and scorpion (Reference & Goodman & Oilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 1630 (6th ed·, 1980); FDA approval. Fed Reg. 3 10.545(a) (2 5)(i)) » Benzyl benzoate is also approved for small additions in food as a medicinal preparation, as well as as a solvent for injectable pharmaceutical formulations, such as the products Faslodex® and Delestrogen® (FDA, Title 21) , vol. 3, ch I, subch B, part 172 (F), ?172·515).

Bitter acid ester is a relatively non-toxic liquid that does not cause damage when applied topically to the eyeball (Grant, TOXICOLOGY OF THE EYE 185 (2d ed., 1974)). Its oral lethal dose Ld50 in humans is estimated to be from 0.5 g/kg to 5.0 g/kg (Gosselin et al., II CLIN Tox OF COMMERCIAL PROD. 1 37 (4th ed, 1 976)). In vivo, benzyl benzoate is rapidly hydrolyzed to benzoic acid or benzyl alcohol. The benzyl alcohol is then oxidized to benzoic acid and then combined with glucuronic acid to form benzoylglucuronic acid or benzylgluconate. A small portion of benzoic acid will bind to glycine to form hippuric acid into the urine (HANDBOOK OF PESTICIDE TOXICOLOGY 1506 (Hayes & Laws, eds., 1991)). The local dexamethasone is mixed with benzyl benzoate to form a homogeneous suspension. A 25 % formulation is easy to inject. When the suspension is slowly injected into the eyeball

(D 60 1379682

m m , endophthalmitis, the island, the skin, therapeutic drugs, insulin, therapeutic drugs, factors, esters

Sympathetic ophthalmia, intermediate uveitis u-type "synthesis, intraocular infections such as Irvine-Gass syndrome. Another embodiment of the invention provides a variety of fertility and/or formulations and uses of the esters and pancreas as a method of insulin delivery controlled by a sugar bed disease.肓 肓 / / 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 式 , , , , , , , , , , , , , This is especially true of proteins. And various other substances (such as steroids, NSAIDs, antibiotic hormone growth anticancer agents, etc.) may also be expected to have a phobia/+ 匕 匕, 汪月附兴/ or tocotrienol and their effective transdermal drugs. Deliver the formula. Avoiding the benefits of oral drug delivery that causes liver enzyme transformation, intestinal breakdown, and stomach stress is the motivation to develop other drug delivery modalities. The first example to start with is the insulin therapeutic used to treat diabetes. The current papers and retrospectives on insulin therapeutics are as follows: Owens, 1 Nature Reviews/Drug Discovery 529-540 (2002); Cefalu, 113 (6A) Am J Med 25S-35S (2002);

Nourparvar et al., 25(2) Trends Pharmacol Sci, 86-91 (2004). Subcutaneous injections such as buccal/sublingual, rectal, intranasal, intrapulmonary, and transdermal may be used to avoid subcutaneous injections of multiple daily pain. However, no fully acceptable alternatives to injection have been established so far. The most promising methods are the intrapulmonary delivery system (Exubra, Pfizer/Aventis; AERxiDMS, Aradigm/Novo Nordisk)' and the osmotic medium containing tocopherol and/or tocotrienol and its esters as therapeutic agents as disclosed herein. New skin delivery formula. 62 1379682 t

The desire for simple and painless insulin and other drug delivery methods through skin has stimulated the production of various transdermal delivery methods such as iontophoresis (electrical introduction), sonic introduction (ultrasonic), and photo-enhancement (pulse) Laser light), heating, transformation (lipid media), and penetrants (such as DMSO, NMP, etc.), but after years of research, there is no complete result. Transdermal delivery methods are believed to be impeded by the relatively poor penetration of the larger hydrophilic peptides, such as insulin, to the skin. However, the present invention provides an effective amount of insulin delivery into the blood by applying an intimate mixture of alpha-tocopheryl acetate to the skin for sustained release. In a mouse research model, when an intimate mixture with alpha-tocopheryl acetate is applied to the mouse skin, an effective amount of insulin can be delivered to the blood of the mouse in a sustained release manner. Because of the long-standing use of tocopherols as a component in sunscreen lotions and cosmetic formulations, there is much literature documenting the use of tocopherols on the skin and its movement through the skin (see, for example, Zondio, 21 (Suppl 3)). Int J Toxicol, 51-116 (2002)). These literature reports that tocopherol can penetrate the skin easily and safely, but no literature has revealed the use of tocopherol as a penetration enhancer or carrier for therapeutic agents to penetrate the skin. There is indeed no mention in the retrospective literature for 102 chemical permeation enhancers in transdermal drug delivery systems for fertility or fertility (Karande et al., 102(13) Proc Nati Acad Sci USA, 4688- 93 (2005)). Tocopherol formulations that can deliver therapeutic drugs to the body easily and efficiently through the skin can be used: dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers of alpha, 0, 7 and 6-tocopherol and their esters (eg, Formates, acetates,

63 1379682

Propionates, linear or branched fatty acid esters of C4 to C20, maleic acid esters, malonic esters, fumarates, succinates, ascorbyl esters ( Ascorbate, or vitamin C) and acid esters; α, 召, r and tocotrienol, dextrorotatory, levorotatory and dextrorotatory and levo isomers and their esters (eg, formate, acetic acid) Esters, propionates, linear or branched fatty acid esters of C4 to C 2Q, maleic esters, malonic esters, fumarates, succinates, Ascorbate and smoke test acid dragons). Further examples of the tocopherols of the present invention provide a variety of formulations comprising 2-acetoxybenzoic acid and its fatty esters with tocopherols, tocotrienols and licorice extracts. More specifically, this aspect provides formulations for injection, ingestion, or topical use of tocopherol and/or tocotrienol and/or licorice extract with ethoxylated albino acid (2 - ABA ) And its main fatty ester compounds to obtain all known pharmaceutical benefits of 2-ABA and its fatty ester compounds, while substantially avoiding the gastric toxicity often associated with 2-guanidine itself. Unlike non-steroidal anti-inflammatory agents that have recently been specifically inhibited against COX-2, such as ce 1 ec ο X ib under the trade name of Celebrex and rofecoxib under the trade name Weikes Etc. It is believed that the experience and experience of 2-ΑΒΑ in the past few decades can properly define the advantages and disadvantages of 2-ΑΒΑ. All the advantages and problems of C0X-2 specific inhibitors are still being explored. In cases of "traditional" NS AIDS such as 2 - ABA, Ibuprofen, praproxine, codopprofen, difenfen, indomethacin, it has been shown to cumulatively affect the stomach and intestines. hurt. Although C0X-2 is specific 5 64 1379682

The formulation has revealed a gastrointestinal problem caused by a lower gastrointestinal problem than 2-ΑΒΑ, but it also faces serious cardiovascular problems associated with C0X-2 specific inhibitors. In terms of 2-ΑΒΑ, its analgesic anti-inflammatory effect is quite miraculous, and it inhibits both COX-1 and C0X-2 relative to the cardiovascular safety problems of inhibitors that only inhibit C0X-2. Sexual chemicals exhibit cardioprotective properties associated with COX-1 inhibition. The cause of gastrointestinal toxicity caused by 2-ΑΒΑ is attributed to its inhibition of COX-1. And it is true that such drugs, such as Xile and Weike, cause a lower degree of gastrointestinal problems because they are only for the inhibition of COX-2. Interestingly, however, the normal intestinal appearance in animals that reject the C0X-1 gene indicates a more subtle cause of gastrointestinal toxicity. The inhibition associated with both COX-I and C0X-2 enzymes can be a major problem. Regardless of the mechanism of gastrointestinal toxicity of 2-pyrene, the advantage exhibited by 2-oxime in other areas of the body is to stimulate the method of seeking the molecule through the gastrointestinal tract without causing harm, but the main mode of administration is ingestion. Three methods have been reported to reduce the uptake of 2-strontium by gastric stimulation. The first and most successful strain was discovered by Rainsford and Whitehouse et al. in 1980 using rats and pigs. It was found that 2-methyl ester, ethyl ester and phenyl esters of ABA hardly caused gastric ulcer. It still has all anti-inflammatory properties of 2-ΑΒΑ (10(5) Agents and Actions, 451-56). Surprisingly, there is no further tracking of the oral intake of 2-ABA esters. Topical application of 2 - A B A for controlling acne, sunscreen and relieving mosquito bites has been reported in the literature (see U. S. 65 1379682)

Patents No. 4,244,948, No. 4,454,122 'No. 3,1 19,739). The second method of lowering the pressure on the stomach suggests that taking foods rich in tocopherols and/or tocotrienols can reduce the formation of damage by about 30% to 40%, which is not as effective as the effect provided by 2-ΑΒΑ. Large, see, for example, Jaari n et al., 13 (Suppl) Asia Pac J Clin Nutr, 5170 (2004); Nafeeza et al., 11(4) Asia Pac J Clin Nutr 309-13 (2002); S ugimoto et Al., 45(3) Dig Dis Sci, 599-605 (2000); Stickel et al, 66(5) Am J Clin Nutr 1218-23 (1997) et al. The third method to reduce gastric pressure is to use 2-antrine with licorice extract (glycemia, glycyrrhizin) for oral administration (Rainsford & Whitehouse, 21 Life Sciences 3 7 1-78 (1977); Dehpour et al . 46 J Pharm Phannacol 148-49 (1994)). Compared to 2-ABA alone, this formulation yields a 66% to 80% reduction in ulceration" never attempted to combine 2-ABA with its esters, tocopherols (or their ethyl ester compounds) and/or Formulation of tocotrienol (or its ethyl ester compound) and licorice extract. The use of direct injection to treat inflammation of the eye or joint avoids stomach damage and systemic inefficiency of the digestive tract. Usually the human 2-ΑΒΑ prescription intake dose (0.650 to 1.3 g) causes a combined concentration of 2-ΑΒΑ/2-hydroxy cuminic acid (2-ΗΒΑ) in the blood of about 20 to 1 μg/ml (Kralinger et al·, 35 Ophthalmic Res 107 (2003)). Studies in rabbit eyeballs have shown that at these plasma concentrations, the concentration of 2-ABA/2-HBA in the vitreous range is between 5 and 10 micrograms per milliliter. Since about 97% of 2-ABA in plasma is hydrolyzed to 2-HBA in 30 minutes, the amount of 2-ABA is much lower than that of 2-HBA. Once the remaining 2-ΑΒΑ reaches the vitreous, in the vitreous environment 5 66 1379682 0

In the middle, the hydrolysis rate of 2-ABA is greatly reduced. The initial concentration of 4 μg/ml will be reduced to half in 15 to 2 hours. 'Since the initial concentration of 2-HBA will be changed from 2-ABA to 2-HBA, it is impossible to properly define the half-life of 2-HBA. The half-life of 2-HBA may be about twice as long as the 2-ABA half-life (Valeri et al_, 6(3) Lens & Eye Toxicity Res 46 5-75 (198 9)). This emphasizes another advantage of direct injection over oral (systemic) medication: injection avoids the problem that 2-ABA loses its base due to hydrolysis when it reaches its target location. It has been shown in the literature 2 that the main anti-inflammatory effect of ABA is that it can reversibly insert the acetamidine into COX 1 and COX 2 enzymes to inactivate it (R〇th & Majerus, 56 J Clin Invest 624-32 (1975)). The ID50 of this reaction in the eye was determined to be between 0.9 and 9.0 μg/ml (Higgs et al, 6 (SuppI) Agents & Actions 167-75 (1979); Kahler et al., 262(3) Eur J Phannacol 261-269 (1994) ° An example of an intraocular injection of a 2-ABA sustained release (ISR) formulation is the injection of 1.0 milliliters of a linaloic acid oil filling containing 1.67 mg of 2-ABA into the vitreous cavity of the rabbit eye. In this study, only 2-HBA was measured, and the initial high peak value of 640 μg/ml was measured within 6 hours. The 2-HBA was reduced to 20 μg/ml in 20 hours and decreased to 5 μg in 120 hours. ML. (K ra 1 ingereta 1 ·, 2 1 (5 ) R etina 5 1 3 - 2 0 ( 2 0 0 1)). Since 2-ABA esters are more hydrophobic, they are used in sustained release formulations. - hydrazine ethyl ester (longer sustained release delivery) has a longer half-life than 2- hydrazine. In addition, 2-nonyl esters or 2-oxime are included in hydrophobic adjuvants such as tocopherol or its acetates. 5 67 1379682 for more sustained release drug delivery

effect. Ingestion of 650 mg of 2-ABA to study the distribution of 2-ABA in blood and human knee synovial fluid, which showed a maximum blood concentration of 2- ABA at 3.3 μg/ml at 7.7 minutes and reached at 10.9 minutes Maximum blood concentration of 2-HBA at 23 μg/ml. And reached a maximum synovial concentration of 2-ABA at 2.5 μg/ml at 19.4 minutes and a maximum synovial concentration of 2-HBA at 14.5 μg/ml at 21.9 minutes (Soren, 6(1) Scand J Rheumatol 17-22 (1977)). At 75 minutes, 2-ABA disappeared from the blood and disappeared from the synovial fluid at 2.3 to 2.4 hours. Intra-articular injection of 20 μg/ml of 2-ABA in an intra-articular injection of 3 ml of synovial fluid in an adult's knee, which also showed an average half-life of 2.4 hours in combination with 2-ABA/2-HBA. (Owen et al,, 38 Br J din Pharmac 347-55 (1 994); Wallis et al., 28 Arthritis Rheum 441-49 (1985)). In addition to the above references to anti-inflammatory treatments of 2-ABA esters and cloth formulations, there are references to the use of 2-ABA esters or 2-ABA as analgesics for skin irritation and wound healing. (US Patent No. 3,1 1,9,739, US Patent Application Pub. No. 2002-0013300; U · S · P at en t No · 4,1 2 6,6 8 1). However, other literature reports show only a small number of results regarding topical use of 2-ABA to soothe mosquito bites or allergic reactions (Balit et al_, 41(6) Toxicol Clin Toxicol 80 1-08 (2003); Thomsen et a 1., 82 Acta Denn

Venereal 30-3 5 (2002)). The best results that can be found are 2-ABA soy solutions for skin that are used to alleviate acute herpes neuralgia or added to the city 68 1379682

2-purine slurry for skin moisturizing lotion (Kochar et al., 47(4) J Assoc Physici ans India 337-40 (1 9 9 9 ; B a 1 akr ishn an et al., 40(8) Int J Dermatol 535-38 (2002)). It should be noted that most of these reported formulations contain water. Therefore, unless these formulations are used immediately after the completion of the formulation, 2-hydrazine may be hydrolyzed in a large amount or the ethyl sulfonyl group on the ester thereof may be removed and removed to become a less effective 2-indole derivative. Therefore, 2-ABA and 2-ABA ester topical formulations containing non-aqueous or non-alcoholic osmotic adjuvants are required for storage. Thus, in still another embodiment of the invention, the compounds used in the formulations are selected from the group consisting of: Group I: 2-acetyloxy benzoate, 2-ethyl hydrazine Ethyl benzoate, ethyl 2-acetoxyacetate, n-propyl 2-ethoxycarbonyl benzoate, isopropyl 2-ethyl acetoxybenzoate, 2-ethoxypropenyl benzoate N-butyl acrylate, isobutyl 2-acetoxybenzoate. Group II: dextrorotatory, levorotatory and dextrorotatory plus levo isomers of α, cold, r and 5-tocopherol and their acetates; right-handed, left-handed and α-, stone, tau and δ-tocotrienol Dextrorotatory plus levo isomers and their acetates; all accompanied by licorice extract or glycerol licorice extract. Thus, one aspect of the invention includes a plurality of novel mixtures consisting of a compound selected from Group I and a compound selected from Group II to provide all necessary therapeutic effects with 2 - A Β 但 but with little or no stomach pressure Oral formula. The approximate composition of these novel oral formulations is from 350 parts by weight of 2-ABA or 400 to 500 parts by weight of 2-ABA ester, 40 to 400 parts by weight of tocopherol or its acetate '35 to 110 parts by weight. Tocotrienol 69 1379682

Or its acetate is added with 400 to 1 400 parts by weight of licorice extract or deglycerol licorice extract. A convenient source of a mixture of tocopherol and tocotrienol can be palm seed oil extract (Carotech Inc, a number of suppliers) or rice bran oil extract (a number of suppliers from Eastman Chemicals). There is evidence that palm seed is a preferred source because of the high content of delta-tocotrienol in palm kernels. (Theriaul t et al., 32(5) Clin Biochem 3 0 9- 1 9 (1 999); Yap et al., 53(1) J Pharm Pharmacol 67-71 (2001)). An exemplary but non-limiting formula is: 3 50 mg of 2-ABA (or 400 mg of ethyl-2-ABA), 200 mg of tocopherol/tocotrienol (palm seed oil pomelo extract), and 1 2 5 mg of licorice extract. Such a formulation can be conveniently contained in a soft gelatin capsule, and if desired, 1 to 8 capsules per day can be taken to relieve inflammation of the body or body of the human or animal body. Another aspect of the invention comprises a novel sustained release mixture of 2-indolyl or 2-indolyl esters with tocopherol or tocopherol acetate for intraocular or intra-articular injection for the treatment of humans or animals Inflammation of the eye or joint. In these formulations, the content of 2-nonyl ester or micro- 2-indole is generally in the range of from 5 to 95 parts by weight, and the content of tocopherol or its acetate is in the range of from 95 to 5 parts. Between the weights. An exemplary but non-limiting formulation is 250 parts by weight of ethyl-2-indole or micro-2-ane and 400 parts by weight of a-dl or d-tocopheryl acetate. Take a small amount of 10 mg to 100 mg of this formula and inject it into the vitreous cavity of the eye through a 20 to 30 gauge needle to provide 2-ΑΒΑ or 70 1379682 over a period of 10 days to 1 year.

Sustained release of the therapeutic concentration of its esters. It is also possible to inject 10 mg to 3000 mg of these formulations into the synovial cavity in human or animal joints to provide an anti-inflammatory treatment for 10 days to 1 year. Still another aspect of the present invention comprises a plurality of from 5 to 95 parts by weight of 2-indene or an ester thereof, 95 to 5 parts by weight of tocopherol, tocopheryl acetate and/or tocotrienol, tocotrienol A novel formulation consisting of acetate as a topical drug that penetrates human or animal skin to relieve inflammation and pain in the skin or joints. Further, the convenient source of both tocopherol and tocotrienol is brown eucalyptus seed oil or rice bran oil extract. A specific undefined formulation ratio is 60 parts by weight of ethyl-2-pyrene or micronized 2-indole and 40 parts by weight of palm seed oil pomelo extract. Without further elaboration, those skilled in the art can benefit from the above, and the invention can be applied to the maximum extent. The examples shown below are for illustrative purposes only and are not intended to limit the remainder of the invention. Example

Example 1. Reaction of 1,3-propanediol at 65 ° C for 96 hours to prepare poly(1,3-propanedicarbonate) I will contain 0.05 g (1.25 mmol (mmole)) of sodium metal 15.2 Glucose (0.2 mol) of 1,3-propanediol was added to 23.6 g (0.2 mol) of diethyl carbonate (bp 128 ° C) to obtain two liquid phases. The reactants were placed in an open vessel, reacted in an oven at 65 ° C and occasionally shaken. At 1 2 hours, the reactants became a 71 1379682 t homogeneous solution weighing 3 8 · 0 g. In the case of complete reaction, the theoretical weight was 20.4 g due to the loss of 0.4 mol (18.4 g) of ethanol. Heating was continued and occasionally shaken so that the weight after 2 hours was 27.0 g, the weight was 23.2 g after 48 hours, the weight was 21.4 g after 72 hours, and the weight was 17.4 g after 96 hours. The product oil was washed with 15 ml of a 5% aqueous acetic acid solution and separated into two phases. The liquid phase of the top layer is the aqueous phase. The volume was washed with 15 ml of water to a lower liquid phase of 10.5 ml to obtain a water-insoluble oil of a 7.5 ml of poly(1,3-propylene carbonate) oligomer.

Example 2, which was reacted with 1,3 -propanediol at 110-150 ° C for 26 hours to prepare poly(carbonic acid-indole, 3-propanediester) II

A mixture of 76 g (1.0 mol) of 1,3-propanediol containing 0.1 g of sodium metal (2.5 nmole) and 118 g (1.0 mol) of diethyl carbonate was heated at 110 °C. A homogeneous solution is formed as soon as the reactants reach 60 °C. After 8 hours of heating, the reactants lost a weight of 48 grams (52% of the theoretical weight of ethanol). The temperature was then raised to 150 °C. After 1 〇, the reactants lost an additional 46 grams of weight. The droplets of this product are completely soluble in water. The obtained 97 g of the oily product was mixed with 6 g of (0·5 5 mol) of diethyl carbonate, and the product solution was heated at 150 ° C and occasionally stirred. After 8 hours, it was found that the syrupy product was partially insoluble in water. The product was washed with 100 ml of a 5 % aqueous acetic acid solution, and then the product was washed four times with 1 ml of water each time to obtain 4 6 · 1 g of a pale yellow viscous oil (yield 46.1/102 = 45%). 5 72 1379682 t

Example 3. Preparation of poly(carbonate-di-1,2-propanediester) from bis-1,2-propylene glycol 67 g (0.5 mol) bis-1,2- which has been reacted with 0.02 g of sodium. Propylene glycol was added to 59.0 grams (0.5 moles) of diethyl carbonate to form a homogeneous solution. The reactants were placed in an open vessel and reacted at 1 °C. After 12, the solution lost 23.4 grams (about 50% of the theoretically 46 grams of ethanol). After an additional 15 hours at 150 ° C, the reactants lost a total of 5 3.2 grams of weight, resulting in a portion of the water-insoluble syrup. The product was washed with 100 ml of a 5 % aqueous acetic acid solution, followed by washing the product four times with 100 ml of water each time to obtain 2 5 · 2 g of a colorless, viscous, water-insoluble poly(di-1,2- A propylene carbonate) oligomer liquid. Example 4. Preparation of poly(carbonate-tri-I,2·propylenediester) from tris-1,2-propanediol 0.1 g of sodium metal was added to 196.0 g (0.5 mol) of tri-1,2-propanediol in. After 5 minutes, the sodium had reacted to leave a pale yellow oil. 59.0 g (0.5 mol) of diethyl carbonate was added to the liquid, and the resulting homogeneous solution was placed in an open flask and heated to 11 °C. After 6 hours, the reactants lost 2 8.0 grams (61% of theoretical weight). The yellow solution was then heated at 1 25 °C for 8 hours until a total of 48 grams of weight (104% of theory) was lost to the reactants. An additional 6.0 grams (0.5 moles) of diethyl carbonate was added and the temperature was raised to 150 °C. After 6 hours, the yellow brown viscous product was washed with 10 ml of a 5 % aqueous acetic acid solution, and then the product was washed four times with 1 ml of water each time to obtain an orange, water-insoluble viscous liquid weighing 48 g. Oligomers. 5 73 1379682 Example 5, Analytical method for measuring the release profile of dexamethasone or propanone triamcinolone released from the sustained release formulation (SRF) of dexamethasone or propylprednisolone

The containers used for the release pattern analysis are marked and the weight of each container is recorded. 3 to 4 grams of a 0.9% physiological saline solution was added to each container and the weight was recorded. The sustained release formulation is then injected or placed into the bottom of the container to record the weight of the sustained release formulation. An additional 0.9% physiological saline solution was added to bring the total weight of the physiological saline solution to 1 gram. Place the beta liters in a 37 °c incubator or water bath. The sample was easily sampled periodically, and a high pressure liquid chromatography (HPLC) was used to measure the release pattern of dexamethasone or acetamidine triamcinolone. The sampling method was performed according to the following steps: using a disposable pipette, carefully draw 8 g of a physiological saline solution containing dexamethasone or acetone triamcinolone from each container and then add 8 g of a 9% physiological saline solution. In each container. The containers were placed at 37 〇c after sampling.

HPLC analysis using a Beckman Gold instrument with an autosampler. Prepare three different dexamethasone or acetone triamcinolone calibrators (c a 1 i b r a t 〇 r s) in water. The calibrators and samples were each injected onto a C 18 column (Rainin, 250 χ 4·6 mm) with a protective column (C i 8, 4.6 mm x 1 cm) and analyzed. Use 45% or 50% acetonitrile/water as the mobile phase to wash the column at ambient temperature for 7 or 6 minutes at a flow rate of 1. 〇ml/min. The detector wavelength used is 238 奈Meter. The concentration of dexamethasone or acetone triamcinolone (residence time, 6-4 minutes) for each sample was calculated from the soft curve of the Beckman Gold instrument using a soft 5 74 1379682 body.

The cleaning procedure for cleaning the HPLC column is set in the HPLC analysis run. After each three or four injections, a sample containing 20 picoliters (PL) of acetonitrile was injected onto the tube and the tube was rinsed with 99% acetonitrile/water as the mobile phase at a flow rate of 1.0 ml/min. Column for 7 minutes. Subsequently, 2 liters of microliters (#丨) of acetonitrile was injected and the column was washed with 45% or 50% acetonitrile/water as a mobile phase at a flow rate of 1.0 ml/min for 7 minutes to balance the column to the original. Mobile phase. The sampling time measured by HPLC analysis and the concentration of the active ingredient (for example, dexamethasone or acetone triamcinolone) were recorded and plotted. The Microsoft Excel software was used to calculate the percent drug release and the drug release. Example 6. Preparation of dexamethasone mixture in poly(1,3-propanedicarbonate) and its release mode

1% by weight of dexamethasone prepared in poly(diethyl carbonate-1,3-propanediester) 1 : 1 part by weight of dexamethasone and 9 parts by weight of poly(carbonic acid-1) prepared in Example 1. , 3-propane diester) 1 mixed. The resulting suspension is stirred at ambient temperature until a homogeneous mixture is formed. The mixture was then dispensed and analyzed to obtain a release pattern as shown in Figure 1. 20% dexamethasone prepared in poly(1,3-propanedicarbonate) 1 : 2 parts by weight of dexamethasone and 8 parts by weight of poly(carbonic acid-1) prepared in Example 1 3-propanediester) 1 mixed. The resulting suspension of suspension 8 75 1379682 was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release pattern as shown in Figure 1. Example 7, dexamethasone mixture prepared in poly(carbonate-1,3·propylenediamine) 11 and its release mode

5% dexamethasone prepared in poly(carbonate-, 3-propane diester) 11: 1 part by weight of dexamethasone and 19 parts by weight of poly(carbonic acid-1) prepared in Example 2 , 3-propane diester) 11 mixed. The resulting suspension is stirred at ambient temperature until a homogeneous mixture is formed. The mixture was then dispensed and analyzed to obtain a release mode as shown in Fig. 2. 10% dexamethasone prepared in poly(1,3-propanedicarbonate) 11: 1 part by weight of dexamethasone and 9 parts by weight of poly(carbonic acid-1) prepared in Example 2, 3-propane diester) 11 mixed. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release mode as shown in Fig. 2.

Example 8, a dexamethasone mixture prepared in poly(carbonate-di-1,2-propanediester) and its release profile were prepared in 5% of poly(carbonate-di-1,2-propanediester) Dexamethasone: 1 part by weight of dexamethasone was mixed with 19 parts by weight of poly(carbonate-di-1,2-propanediester) prepared in Example 3. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release mode as shown in Fig. 3. 10% dexamethasone prepared in poly(carbonate-di-1,2-propanediester): 5 76 1379682

One part by weight of dexamethasone was mixed with 9 parts by weight of the poly(carbonate-di-1,2-propanediester) of Example 3. The suspension is stirred at ambient temperature until a homogeneous mixture is formed. The mixing analysis is then dispensed to obtain a release pattern as shown in Figure 3. 2 parts by weight of dexamethasone and 8 parts by weight of poly(carbonic acid-di-1,2-propene in Example 3) prepared in poly(carbonate-di-1,2-propanediester) Diester) mixed. The suspension is stirred at ambient temperature until a homogeneous mixture is formed. The mixing analysis is then dispensed to obtain a release pattern as shown in Figure 3. The produced product is prepared and subjected to the preparation of the mixed product prepared by dexamethasone

Example 9, a hydrate prepared in poly(carbonic acid-tris-1,2-propanediester) and its release mode were prepared in 5% of poly(carbonic acid-tris-1,2-propanediester) One part by weight of dexamethasone was mixed with 19 parts by weight of the poly(carbonic acid-tris-1,2-propylene diester) in Example 4. The suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed to obtain a release pattern as shown in Fig. 4. One part by weight of dexamethasone and 9 parts by weight of poly(carbonic acid-triple-1, 2 - in Example 4) prepared in poly(carbonic acid-tris-1,2-propanediester) Propylene ester) mixed. The suspension is stirred at ambient temperature until a homogeneous mixture is formed. This mixing analysis is then dispensed to obtain a release pattern as shown in Figure 4. Dexamethasone: the prepared and processed sesamethasone. The prepared product was prepared and subjected to Example 10, a dexamethasone mixture prepared in benzyl benzoate and its release 77 1379682 20% dexamethasone prepared in benzyl benzoate was mixed with 2 parts by weight of dexamethasone and 8 parts by weight of benzyl benzoate. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release pattern as shown in Figure 5.

A formulation containing 5% and 50% dexamethasone in benzyl benzoate was prepared in a manner similar to the conditions for preparing the 20% formulation, except that the weight ratio of dexamethasone/decyl benzoate was different. After preparing a mixture of 5% and 50% dexamethasone in the taucarboxylic acid tau ester, the resulting mixture is divided into small amounts, and the analysis using the small amount of the package has been obtained as shown in FIG. Release mode.

Dexamethasone in decyl phthalate forms a homogeneous suspension. A formulation with a content of 25 % can be easily injected. When the suspension is slowly injected into the posterior segment of the eye, a uniform spherical storage mass (storage bin) is formed in the vitreous. Subsequently, the dexamethasone is slowly placed in the vitreous humor of the posterior segment of the eye. Dexamethasone and benzoic acid esters will eventually be metabolized into by-products and excreted into the urine. Example 12, a dexamethasone mixture prepared in diethyl dibenzoate and its release mode, 10% dexamethasone in diethylene dibenzoate, 1 part by weight of dexamethasone (Dex) was mixed with 9 parts by weight of diethylene dibenzoate. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release pattern as indicated by 78 1379682 in Figure 6. In addition to the different weight ratios used, other conditions were similar to the conditions for preparing 10% dexamethasone/dibenzoic acid diethyl ester to prepare 5% and 25% dexamethasone/dibenzoic acid diethyl ester. Mixture formula. The resulting mixture is then dispensed and subjected to a release mode analysis as described above to obtain a release pattern as shown in Fig. 6.

Example 13, a mixture of flubenzixonolone prepared in diethylene dibenzoate and its release profile prepared in 5%, 10% and 25% of the dibenzoic acid diethyl ester, acetone triamcinolone Long, 5, 1.0 or 2.5 parts by weight of triamcinolone acetonide is mixed with 9.5, 9.0 or 7.5 parts by weight of diethylene dibenzoate, respectively. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and subjected to release mode analysis as described above. The release mode as shown in Fig. 7 is obtained.

Example 14, Dexamethasone Mixture Prepared in d-Tocopherol or d, Beta-Tocopheryl Acetate and Its Release Mode To prepare 10% dexamethasone in d-tocopherol, 1 part by weight Dexamethasone (Dex) is mixed with 9 parts by weight of d-tocopherol. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release mode as shown in Fig. 8. For the preparation of 20% dexamethasone in d-tocopherol, 2 parts 8 79 1379682

The weight of dexamethasone is mixed with 8 parts by weight of d-tocopherol. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release pattern as shown in Figure 8. To prepare 50% dexamethasone in d,l-tocopheryl acetate, 5 parts by weight of dexamethasone was mixed with 5 parts by weight of d,1-tocopheryl acetate. The resulting suspension was stirred at ambient temperature until a homogeneous mixture formed. The mixture was then dispensed and analyzed to obtain a release pattern as shown in Fig. 8. Example 15. Production of a solid drug delivery system containing dexamethasone and dibenzoic acid diethylene glycol and its release mode The dexamethasone powder and diphenyl phthalate are used in a weight ratio using a mortar and pestle. mixing. The mixture was placed in a Parr pellet press having a diameter of 2 mm, and a solid pellet suitable for implantation was prepared at 25 °C. Subsequently, the newly prepared pellet was weighed on a micro scale before the in vitro pharmacokinetic analysis as shown in Fig. 9. Example 16. Production of a solid drug delivery system containing dexamethasone and benzyl dibenzoate and its release mode The dexamethasone powder and dibenzoic acid diester were thoroughly mixed in a weight ratio using a mortar and pestle. The mixture was placed in a Parr tablet having a diameter of 2 mm, and a solid pellet suitable for implantation was prepared at 25 °C. Subsequently, the newly prepared pellet was weighed prior to a microbalance before performing the in vitro pharmacokinetic analysis as shown in Figure 1. 80 1379682 Example 17, Production of a solid drug delivery system containing dexamethasone and tocopheryl succinate and its release profile

The dexamethasone powder and the tocopherol succinate powder were thoroughly mixed in a weight ratio of 50/50. The well-mixed mixture was filled into a single barrel extruder and heated at 65 ° C for 1 hour, and the mixture was extruded through a 1 mm opening. The extruded mixture strips were cut into tiny pellets of various sizes suitable for implantation for in vitro pharmacokinetic analysis as shown in Figure 11. Example 18, combination formula

A combination of two or more drugs can be conveniently formulated using an adjuvant such as tauphthalic acid taurate to provide sustained and controlled release of the active drug. Changes in the volume, concentration, and percentage of such components are the duration and therapeutic concentration that affect drug release. For example, in a 20% formulation of dexamethasone: sepfoxacin in a ratio of 1:1 mixed with benzyl benzoate, the release patterns of the two drugs are similar, and the release time is about 28 to 3 5 days. The release patterns of the two drugs are shown in Figure 1 2 A. Another useful composition comprises dexamethasone and ciprofloxin, the ratio of dexamethasone: sepfenxin being 3:1. The release time of each drug was significantly prolonged. As shown in Fig. 12B, the release time of dexamethasone was about 60 days, while the time of Sepfersin was longer. Example 19, Pharmacokinetics and Metabolism of Injection Formula Containing Dex 81 1379682

For the in vivo release of dexamethasone in vivo, the experiment was carried out using a composition of 25% by weight of dexamethasone (DB) in benzyl benzoate. Volume 25 μl (low dose) and content 6 mg of dexamethasone, 50 μl (high dose) and 12 mg of dexamethasone. Benzoate benzoate was used as a placebo. In vivo release of the dexamethasone/benzoic acid T-ester (DB) composition was studied in 24 rabbits. Twenty microliters of the 25% DB composition was injected into the posterior segment of the eye of one of the 12 animals, and a placebo was injected into the other eye. Another 12 animals were injected with 50 μl of this DB composition in one eye and 50 μl of benzoate taurate placebo in the second eye. Animals were euthanized at appropriate time points and surgically removed for crystalloid samples. The concentration of dexamethasone was determined by high pressure liquid chromatography (HPLC) as described in Example 5. At high doses, the highest concentration of dexamethasone was released during the first week of the implant composition, and the average from day 7 to day 90 was 5.56 μg/ml, and on day 90. The average value slipped to 1.85 μg/ml. In terms of low dose, the average concentration of dexamethasone from day 7 to day 60 was 2.8 μg/ml and slipped to 0.8 μg/ml. See Figure 13. Dexamethasone was not detected in the eyeball as a control group. Clinically, 24 animals that received placebo or low and high dose DB compositions did not develop inflammation or infection throughout the course of the experiment. The slit lamp ophthalmoscope and fundus examination are used every two weeks to check the animals. No cataract, vitreous or retinal abnormalities were observed. According to histopathology, three animals were injected into one eye for 2 5

82 1379682

The DB composition was microlitered and 25 microliters of placebo (BB) was injected into the other eye. In addition, three animals were injected with 50 microliters of the DB composition in one eye and 50 microliters of placebo (BB) in the other eye. The animals were tracked weekly on a weekly basis and the animals injected with the low dose composition were killed on day 30 and the high doses of the animals were sacrificed on day 90 for pathological analysis. The eyeball was fixed with 10% buffered formalin and examined after staining of the eyeball with Η & E. The anterior segment of the eye including the cornea, anterior chamber, iris, ciliary muscle and lens is normal. Pigment epithelial cells, Bruch's membrane and choroids are within the normal range, see Figure 14. There was no significant difference in histopathology between the treated eyeballs and the control group.

To further examine the in vivo anti-inflammatory effect of the DB composition, 25 microliters of a 25% DB composition was injected into three monocular glasses of New Zealand white rabbit weighing between about 3 kg and 3.5 kg. After 24 hours, 2.5 mg of bovine serum albumin (BSA) was injected into both eyes. Observe these animals daily and perform an eye exam. Between 10 and 14 days, uveitis occurs in the eyeball that is not protected by DB with a severe fibrotic response. In the eyeballs in which D B was injected, only mild or no inflammatory reactions occurred. In terms of histopathology, the unprotected eyeballs present chronic and acute inflammatory cells in the uveal tissue, anterior chamber and vitreous cavity. In the protected eyeball, a slight inflammatory appearance with a small number of round cell infiltrations appears in the choroid. The cornea, iris, retina and choroid are well organized, see Table 1 below. 83 1379682 Table 1. Inflammatory response in New Zealand white rabbits NZW Day 0 Day 14 1 OD BS A/DB * 3 + OS BS A 0-1 + 2 OD BSA 3-4 + OS BS A/DB Slight 3 OD BSA/DB 0 OS BSA 4 + BSA: bovine serum albumin; DB: 25% dexamethasone/benzoate taurate; 〇D: right eye; 0S: left eye; 0-4: inflammation of the posterior segment Severity; 4+ is the maximum

The other three New Zealand white rabbits were injected intravenously (IV) with 10 mg of calf serum albumin (B S A). Twenty-one days after the injection, 0.5 mg of BSA/0.1 ml of physiological saline was injected subcutaneously, and all animals showed a strong (+4) Arthrace reaction (Arthusreacti ο η), which showed that the animals exhibited BSA. Systemic immune response. On day 30, 25 microliters of 25% DB composition was injected into a single eyeball of each animal' and after 24 hours, 0.5 mg BSA/0.1 ml normal physiological saline was injected into both eyeballs. The unprotected eyeball develops severe uveitis and continues to swell for the next 7 to 10 days, while the protected eyeball is judged to be in a normal condition. On day 60, the repeated skin test showed that the (+ 4) 5 84 1379682 Arthurs reaction remained intact, and the normal physiology of 0.5 mg BSA/O. 1 ml was still similar to the third. The protective effect observed at 0 days. These studies suggest that the DB composition has an immediate and sustained protective effect in the experimental eyeball. When the animals were given 0.5 mg BSA/0.1 ml normal saline solution on the 90th day, uveitis occurred in all eyes, but the inflammation of the eyeball protected by (DB) was less serious. Table 2 below. The 25 ml DB lasts 60 days of anti-inflammatory protection. On the 90th day, the concentration of dexamethasone in the eyeball

Table 2. Inflammatory response in protected and unprotected New Zealand white rabbit eyeballs NZW Day 0 Day 14 Day 30 Day 60 Day 90 OD BS A 3-4 + 3-4 + 3- 4 + OS BS A/DB* 0 0 2-3 + 2 OD BSA 4 + 3-4 + 3 + OS BS A/DB Slight 0 + 2-3 + 3 OD BSA 4 + 4 + 4 + OS BS A/ DB 0-1 + 0 2-4 + BSA: bovine serum albumin; DB: 25% dexamethasone/benzoate taurate; 〇D: right eye; OS: left eye; 0-4: inflammation of the posterior segment of the eye Severity; 4+ is the maximum

85 1379682

Similarly, three other New Zealand white rabbits were injected intravenously with 10 mg of BSA. After 24 hours, a single eyeball of each animal was injected with 50 microliters of a 25% DB composition. At the 3rd month (90 days), the intradermal skin test caused a +4 response. One week later, 0.5 mg BSA/0.1 μl of normal physiological saline was injected into both eyes of each animal. The protected eyeball (25% DB injection at 50 microliters) showed little or no clinical uveitis compared to the unprotected eyeball as a control group. This result shows that dexamethasone can slowly protect the eyeball for up to three months when the eyeball is stimulated by B S A. See Table 3 below.

Table 3. Continuous protection in the eyeballs of protected New Zealand white rabbits NZW Day 0 Day 90 1 OD BSA/DB* 0-1 + OS BS A 4 + 2 OD BS A/DB 0 + OS BSA 3 -4 + 3 OD BSA/DB 0-1 + OS BSA 4 + BSA: bovine serum albumin; DB: 25% dexamethasone/benzyl benzoate; OD: right eye; OS: left eye; 0- 4: severity of inflammation in the posterior segment of the eye; 4+ is the maximum value of 86 1379682. Example 2, pharmacokinetics and metabolism of the formulation containing TA, 25% by weight of acetamtrozine used in benzyl benzoate Long (TA) composition (TA/B) was tested: 25 microliters in volume and containing milligrams of acetone triamcinolone (TA), and a volume of 5 microliters and containing " gram of acetone triamcinolone. Benzyl benzoate (BB) was used as a placebo. The in vivo release of acetone triamcinolone (TA) was studied in 27 rabbits. 25 microliters of the 25% composition was injected into 12 animals, of which only the back of the eye was in the eye' and 25 microliters of benzoic acid ester (BB) was injected into the other eye. Another 12 animals were injected with the same composition in microliters in the posterior segment of the eye and 5 μL of the awkward T ester in the second eye. At appropriate time points, the animals were euthanized and surgically removed for a sample of the glass (n = 3 at each time point) to determine the TA by high pressure liquid chromatography (HPLC) as described in Example 5. concentration. The average vitreous TA concentration for the 50 micro TA/B composition was 3.25 μg/ml after 24 hours of implantation; 2 to 45 μg/ml at one month; 1.45 μg/ml at three times; and six months The average vitreous concentration of the TA was 2. μg/ml during the entire period of six months. The average glacial TA concentration of the animals injected with 25 microliters of the TA/B composition was 178 micrograms per milliliter after 24 hours of implantation; 1.31 micrograms per milliliter at one time; 0. 8 micrograms per month at one month. ML. 0.4 μg/ml for three hours; and 36 μg/ml for six months. The average glass vitreousity of the TA was 〇 micrograms/ml during the entire period of six months. No TA was detected in the eye of any control group, see Figure 15. In terms of the dose of 25 ml, the observation of the western 7.0 mM A 50 acid in the 270-day period was carried out for the month at 17 glass weeks at 93 to 5 87 1379682

HPLC analysis. See Figure 16 for a sustained release of dexamethasone. Clinically, the animal's eyeball is completely inactive and the component is judged to be biocompatible. Example 22. Continuous release of a dexamethasone/da tocopheryl succinate coating on a stainless steel surface and a heart stent. A dexamethasone was applied to the surface of two stainless steel tubes and two commercially available cardiac stents: acetone: tocopherol The diester ratio is a 2:8:1 (wt) mixture coating. Soaking and oven drying can be utilized to achieve the coating step. In the HPLC analysis, the elution step of dexamethasone can be done in a 20 ml liter of distilled water bottle, and a total volume of 75 % is exchanged during each analysis. Referring to Figure 17, tocopheryl succinate exhibits an effective coating medium that can be used as a stainless steel surface to control drug release. This method can be extended to different materials and surfaces, such as wood, glass, various metals, rubber, synthetic surfaces such as Teflon, plastic and polyethylene pipes, and so on. Example 23. Formulation of cyclosporin in tocopherol succinate To study the in vitro release of dha tocopherol: cyclosporin A in a ratio of 25:75, cyclosporin and tocopherol The succinate was mixed and the mixture was extruded through a 790 micron hole at 25 °C. One milligram of this material was placed in a container of 10 ml of distilled water and divided into small amounts to carry out the above dissolution test. Referring to Figure 18, it was observed that the extended sustained release effect was linear during the 272 day period. In order to study the release pattern in the body, surgically, 0.75 mg of 5 89 Λ 1379682

Tocopheryl succinate: A 25:75 mixture of cyclosporin was implanted into the right anterior chamber (A C) of a 4 kg New Zealand female white rabbit. At the above time, the body fluid of the anterior chamber was taken for HPLC analysis of CsA in aqueous humor, see Fig. 19. In addition, a mixture of 5.0 mg of tocopheryl succinate: 25:75 cyclosporine was surgically implanted into the left posterior chamber (P S) of a 4 kg New Zealand female white rabbit. At the above time point, the vitreous humor of the posterior chamber was taken for HPLC analysis of CsA, see Figure 20. In another in vivo release profile study, 30 mg (3 x 10 mg) of a 25:75 tocopheryl succinate: cyclosporin formulation was extruded from a 1 mm hole at 25 °C. After the tissue was wiped with 〇 - 5 % lidocaine, the extruded segments were inserted into the abdominal cavity of a male adult Sprague-Dawley rat through a 3 mm hole using a trocar. A cardiac puncture was performed to obtain a sample of LC MS MS analysis of blood CsA, see Figure 21. Implants of cyclosporin-tocopherol succinate can be injected into different organs of Sprague-Dawley rats using a trocar to determine the distribution of cyclosporin. More specifically, different weights of 20:80 tocopheryl succinate: cycloheximide extrudate were implanted. After the animals are sacrificed and the tissues are harvested, all tissues are placed in a tissue concentrator for 48 hours, and crushed and soaked in 1 ml of methanol containing 10 ng/ml CsD. Analysis was carried out by phase chromatography mass spectrometry. The measured C s A lines are shown in Tables 4 and 5 below. Abbreviations: "ant" is an abbreviation for "anterior"; "post" is an abbreviation for "posterior"; "hemj is 8 90 1379682 hemisphere j.

Table 4. Distribution of cyclosporin in the liver and brain of rats Liver #1: Upper lobe, killed on the fifth day, implanted 2 mg in tocopherol in the right third of the middle lobe 80% CsA* in the diester. Dry tissue (mg) CsA (ng/ml) CsA (ng/mg) Right third 71.4 mg 2540 35.6 Middle one 119.4 19 1 1.6 Left three One of the 88.4 184 2.1 the middle third of the right * 83.3 2360 28.3 The left third 88 87 8 10 The left third 49.2 2620 53.2 Blood na 0 na Observation: When the implant is implanted in the middle lobe, the detect Measurement of CsA distribution in the upper and middle leaves * Liver # 2: Lower lobe, killed after 24 hours, injected with 2 mg of implant right quintile 99.3 254 2.6 Right middle fifth 59.6 144 2.4 Inclusion* 138.8 2420 Left middle fifth 77.5 17 10 22 Left fifth 53.5 278 5.2 Observation: The experimental animals killed in 24 hours showed a higher concentration in the part of the liver containing the implant. Brain #1: After 2 hours of killing, inject 1 mg of the formula 91 1379682

Left cerebral anterior hemisphere 47.2 72.1 15.3 Left cerebral hemisphere 79.3 180 2.3 Right cerebral anterior hemisphere * 52.7 1190 22.6 Right cerebral hemisphere 60.8 385 6.3 Blood na 0 na Observation: Even if the implant is placed in the right anterior hemisphere, CsA distribution can still be found in both cerebral hemispheres* Brain #2: 1 mg formulation in the right cerebral hemisphere* Left cerebral hemisphere 42.2 478 11.3 Left cerebral hemisphere 68.6 127 1.9 Right cerebral anterior hemisphere* 73.9 401 5.4 Right cerebral hemisphere 113.7 96 0.8 Blood na 0.29 η a Observation: Similar to Brain #1, the left cerebral anterior hemisphere showed a higher concentration* Implantation position Table 5. Distribution of cyclosporin in rat spleen and kidney Spleen, the direction of the site is from right to left. There is 1 mg of implant in the site #7. Dry tissue (mg) CsA (ng/ml) CsA (ng/mg) Part # 1 10.3 217 21.1 Part # 2 16.2 72.5 4.5 Part # 3 12.9 17.7 1.4 Part # 4 24.9 62 2.5 Part # 5 22.5 72.9 3.2 5 92 1379682 Part # 6 26.8 101 3.8 Part # 7 * 29 1800 62 Blood cannot be detected (na) 0 Unable to detect Inspect: Show higher distribution of kidneys at opposite poles of the spleen, implant one-third of 0.75 mg of implant in the lower third. 156.8 3 14 2 Intermediate 85.5 333 3.9 Lower third* 106.1 165 1.6 Observation: CsA is distributed throughout the kidney* implantation site

Example 23, delivery of insulin via skin

Several studies of injectable and transdermal formulations were compared in a mouse model. One milligram of porcine insulin was intraperitoneally injected into a mouse body. A sharp drop in glucose concentration was observed within half an hour and became a symptom of hypoglycemia after one hour. The symptoms of hypoglycemia continue to be below the detectable concentration and the animals are unable to recover. When 1 mg of porcine insulin was mixed with 0.1 ml of phenolic acetate and intraperitoneally injected, a noticeable decrease in blood glucose concentration was observed for up to 3 hours, and the animals maintained hypoglycemia and did not rise. Abdominal glucose instillation does not reverse the hypoglycemia symptoms. One milligram of swine insulin was mixed with 0.1 ml of tocopheryl acetate and topically applied to the skin of a depilated mouse. It was observed that the glucose concentration slowly decreased and the lowest glucose concentration was detected at 5.5 hours. It was observed that the blood glucose returned to the pre-treatment concentration at 24 hours and 48 hours. Intraperitoneal injection of tocopherol can delay the hypoglycemia caused by insulin in 5 93 1379682. Transdermal insulin/tocopherol acetate produces an effect that slows the blood glucose concentration back slowly to the pre-treatment concentration after 24-48 hours. Sustained release of transdermal insulin was observed (data not shown).

Pig insulin (20 mg) was mixed in 199 mg/ml tocopheryl acetate and a paste (or gel) was formed and applied to a depilatory mouse in the following manner. The back. Apply 3 9 · 8 mg of insulin/tocopheryl acetate paste to 3.6 mg of insulin to mouse # 1; apply 75.2 mg of insulin/tocopheryl acetate paste to mouse #2 , equivalent to 6.9 mg of insulin. The blood glucose concentration in the tail was measured using the "True Track s m a r s y s t e m" blood glucose intensive meter at Home Diagnostics, Inc. at the time interval shown in Fig. 22. The decrease in glucose concentration was observed as soon as half an hour after transdermal administration, and the concentration continued to be low for up to 15 hours. After 24 hours, the glucose returned to the pre-treatment concentration and then returned to the hyperglycemic state for the next 24 hours. This experiment demonstrates the sustained release of insulin for transdermal administration. Drugs that can be delivered by this method include: analgesics, anesthetics, anesthetic analgesics, angiostatic steroids, anti-inflammatory steroids, angiogenesis inhibitors, non-steroidal anti-inflammatory agents, anti-infectives Agent, antifungal agent, antimalarial drug, antituberculosis agent, antiviral agent, alpha male agonist, beta adrenergic blocker, carbonic anhydrase inhibitor 'mast cell stabilizer, miotic agent, Prostaglandins, antihistamines, anti-microtubule agents, anti-tumor agents, anti-apoptotic agents, aldose reductase 5 94 1379682

Inhibitors, antihypertensive agents, antioxidants, growth hormone granule resection agents, adenine nucleoside receptor antagonists, adenosine nucleoside inhibitors, saccharification antagonists, anti-aging peptides, topological differences Constructant, antimetabolite, pituitant, anti-androgen agent, anti-estrogen gene gene activation inhibitor, telomerase inhibitor, antibody or partial antisense oligonucleotide, fusion protein, luteinizing hormone Release of hormones to promote gonadotropin release hormone inhibitors, tyrosine kinase inhibitor growth factor inhibitors, ribonucleoside reductase inhibitors, cytotoxic agent-2 therapeutic agents, neurotensin antagonists , peripheral type σ-ligand ΕΤΑ/receptor antagonist, hypoglycemic agent, anti-glaucoma agent, anti-staining enzyme, weight control drug, anemia therapeutic agent, antiemetic, leukopenia therapeutic agent, tumor caused Hypercalcemia therapeutic agent blood, anti-proliferatives, immunosuppressant repair agent, psychotherapeutic agent, Aptamer produced by Eye tech, Lucentis, preparation, islet produced by Genentech , human insulin, glucagon-like peptide-1 (enzyme (Byetta) produced by glp Amylin, Inc.. For the practitioner, the subject, or the related art, it is intended to be used in the practice of the present invention. Various modification changes of the above methods are also within the scope of the patent application scope. Agent, glass deaminase enzyme inhibition, carcinogen, reaction agent, epidermis, mediator, endothelial color neutrophil, anticoagulation, tissue adaptation Sub-RNA inhibition -1) and the corresponding, can be clearly belonged to the following [simplified description of the schema] Figure 1 shows two dexamethasone (Dex) / poly (丨, 3-carbonate formula of dexamethasone dissolution mode. Diester) 1 95 1379682 Figure 2 shows the dissolution mode of dexamethasone in two Dex/poly(1,3-propylene carbonate) II formulations. Figure 3 shows the dexamethasone dissolution mode for three Dex/poly(di-1,2-propylene carbonate) formulations. Figure 4 depicts the dexamethasone dissolution mode for two Dex/poly(tri-1,2-propylene carbonate) formulations.

Figure 5 is a graph showing the dissolution mode of dexamethasone released from three Dex/benzyl benzoate formulations. Figure 6 is a graph showing the dissolution mode of dexamethasone released from three Dex / dibenzoate diester formulations. Figure 7 is a graph showing the dissolution pattern of acetone triamcinolone liberated from three acetone triamcinolone/dibenzoate diethylene glycol formulations. Figure 8 is a graph showing the dissolution mode of dexamethasone released from three formulations consisting of Dex/d-tocopherol and dl-tocopheryl acetate.

Figure 9 is a diagram showing the dissolution mode of dexamethasone released from a Dex/dibenzoic acid diethyl ester formulation. Figure 10 is a graph showing the dissolution mode of dexamethasone released from a Dex / benzyl benzoate formulation. Figure 11 is a graph showing the dissolution mode of dexamethasone released from a Dex/tocopherol succinate formulation. Figure 1 2 shows a formulation of D e X / cefofloxacin in a ratio of 1:1 in the benzyl benzoate (Fig. 12A), and a mixture of Dex/West in the taurate The dissolution rate of 96 1379682 dexamethasone and cefofloxacin released by the Pfoxacin ratio of 3:1 (Fig. 12B). Figure 13 is a graph showing the concentration of dexamethasone released from the two dexamethasone (D ex ) formulations mixed with benzyl benzoate into the vitreous anterior chamber fluid. Figure 14 shows the rabbit eyeball tissue section on the third day after injection of a formulation containing 25% dexamethasone in benzyl benzoate in the posterior segment of the eye. Fig. 15 shows the concentration in the vitreous of acetone triamcinolone released from the acetone triamcinolone (TA) / benzyl benzoate composition.

Figure 16 shows the in vivo release of dexamethasone released into the aqueous humor by a Dex/dl-α-tocopherol succinate formulation. Figure 17 shows the dissolution mode of dexamethasone released by a Dex/acetone/tocopherol succinate formulation coated on a solid surface. Figure 18 shows the cyclosporin dissolution profile released by a cyclosporin/tocopherol succinate formulation. Figure 19 shows the in vivo release profile of cyclosporine released from a tocopherol succinate/cyclosporin formulation in the anterior chamber of the New Zealand white rabbit eye.

Figure 20 shows the in vivo release profile of cyclosporine released from the tocopherol succinate/cyclosporin formulation in the posterior segment of the New Zealand white rabbit eye. Figure 21 shows the in vivo release profile of cyclosporine released from a tocopherol succinate/cyclosporin formulation implanted in the peritoneal cavity of rabbits. Figure 22 depicts the in vivo blood glucose concentration of a mouse administered with an insulin skin absorption formulation mixed with tocopheryl acetate. [Main component symbol description] None 5 97 1379682

Claims (1)

Announcement 1379682 - ifi. 1 (I 豕帛 Patent 豕帛: TP Amendment 10, Patent Application Range: 1. A pharmaceutical formulation for sustained release of at least one active drug in the eye, the pharmaceutical formulation consisting of at least one biological phase And a biodegradable adjuvant and at least one active drug or a pharmaceutically acceptable salt thereof, wherein the formulation can be implanted by intraocular injection; wherein the ratio of the adjuvant is at least 2% of the formulation Wherein the adjuvant provides sustained release of the active drug; Wherein the adjuvant is selected from the group consisting of benzyl benzoate; a monoester, a diester and a trisole formed from (9-acetamidine citrate and (:! to a linear or branched fatty alcohol of CiO) Ester; a monoester or diester formed from 0 acetic acid citrate or a linear or branched fatty alcohol of <9-propion citrate or 0-butan citrate and (^ to C1() Triesters; dimethyl sulfone; α, /5, r and 5-tocopherol dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers and tocopherol esters, fertility esters selected from formates, Acetate, propionate, C4 to C20 linear or branched fatty acid esters, maleic esters 'malonates, fumaric acid vines, succinates, Ascorbate and nicotinic acid esters; dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers of α, lut, τ and 5-tocotrienol, and esters of tocotrienol, esters of tocotrienol a linear or branched fatty acid ester selected from the group consisting of formates, acetates, propionates, C4 to C2, maleates, malonic esters, fumarates 'Succinic acid esters, resistant Ester with nicotinic acid esters; and wherein the active drug from the formulation exhibits at least 4 days of sustained release 991,379,682. 2. A pharmaceutical formulation for the sustained release of an active drug in the eye of a patient, the pharmaceutical formulation comprising at least one biocompatible and biodegradable adjuvant and at least one active drug or pharmaceutically acceptable thereof a salt composed of a group selected from the group consisting of α, cold, r and <5-tocopherol, dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers and tocopherol esters, fertility The phenolic esters are selected from the group consisting of phthalates such as acetates, propionates, linear or branched fatty acid esters of C4 to C20, maleic esters, malonic esters, and anti-butene. Diesters, succinates, ascorbates and nicotinic acid esters; dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers of alpha, cold, gamma and 6-tocotrienol and tocotrienol Esters, esters of tocotrienols selected from the group consisting of phthalates, acetates, propionates, linear or branched fatty acid esters of C4 to C2, maleic esters, C Diesters, fumarates, succinates, ascorbates and nicotinic acid esters; benzyl benzoate; from benzoic acid and Ci An ester formed by a linear, branched or cyclic fatty alcohol of C2, wherein one of several hydrogen atoms of the aliphatic chain is replaced by 0H; from acetonitrile or (9-propion citrate) Or a monoester, diester or triester of <9-butyric acid citrate and a linear or branched fatty alcohol of the mountain to C1(); a linear or branched chain of citric acid and (:! to CI0) a monoester, diester, and triester formed by a chain fatty alcohol; wherein the formulation exhibits an in vitro or in vivo dissolution pattern, wherein the release is between 4 days and 105 days (or 4 days to 365 days) 2% to 100% active drug. 100 1379682 3. The pharmaceutical formulation according to claim 1, wherein 2% to 60% of the active Tsai is released during the period of at least 3 65 days. 4. The pharmacy according to claim 1 The formulation comprises from 5% to 50% of the active drug of the implant. 5. The pharmaceutical formulation according to claim 1, comprising 5% to 80% of the active drug, and the adjuvant has a degree ranging from 20% to 99.5%. between. 6. The pharmaceutical formulation according to claim 1, wherein the substance is selected from the group consisting of analgesics, anesthetics, numbing agents, vascular stability steroids, anti-inflammatory steroids, vascular preparations, Non-steroidal anti-inflammatory agents, anti-infective agents, anti-fungal agents, anti-tuberculosis agents, antiviral agents, alpha-type androgen-promoted adrenaline blockers, carbonic anhydrase inhibitors, mast cell stabilization Agent, prostaglandin, antihistamine, anti-microtubule, anti-tumor anti-apoptotic agent, aldose reductase inhibitor, antihypertensive agent, agent, growth hormone antagonist, vitreous resection agent 'adenine Nuclear antagonist, adenine nucleoside deaminase inhibitor, saccharification antagonistic aging peptide, topoisomerase inhibitor, antimetabolite, alkylating agent, antiestrogens, oncogene activation inhibitor The telomere is between 4 and Μ. The concentration is the concentration of the corresponding active drug, the anti-malarial agent, the anti-malarial agent, the β-dose, the tumor agent, the anti-oxidation receptor, the anti-and anti-androgen inhibitor 101 1379682, the antibody or the partial antibody, Antisense oligonucleotides, fusion proteins, tyrosine kinase inhibitors, epidermal and growth factor inhibitors, ribonucleoside reductase inhibitors, cytotoxins, mediators of Jingjing-2, neurotensin antagonists, Peripheral σ-ligand, endothelium | ρ I ETA/receptor antagonist, hypoglycemic agent, anti-glaucoma agent, anti-chromatin sputum master / decoration enzyme, anemia therapeutic agent, antiemetic, neutrophil Leukopenia., Α 士 〇 〇 〇 、 、 、 、 、 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士Toxin toxic sound # East and psychotherapeutic agents. 7. The pharmaceutical formulation according to claim 6, wherein the active drug is one or more steroid anti-inflammatory agents selected from the group consisting of: 21-acetoxy ketamine (2l_aCet) 〇xypregnen〇l〇ne), alclometasone, algestpronone, amcinonide, beci〇rnethasone, betamethasone ), budesonide, clopenemone (chloroprednisone), clobetasol, clobetasone, ci〇c〇rt〇i〇ne, cloprenol, corticosteroids Corticosterone), cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone ), dexamethasone 21-acetate, dexamethasone 21-phosphate di-Na salt, diflurane 102 1379682 diflorasone, difluoro-corbrin Diflucortolone, difluprednate, glycyrrhetinic acid (enox〇l〇ne) 'fluazacort flucloronide, flumethasone (flumethasone), flunisinlide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone ), fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, Fluticasone propionate, formocortal, hacinnonide, dripized betasopropionate (halobetasol) Propionate), halometasone, haloped halope vinegar (halopredone acetate), hydrocortamate, hydrocortisone, loteprednol etabonate, maz Mazipredone, medrysone, meprednisone, methylprednisolone 'mometasone furoate, paramethasone , prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate ), prednisone prednival, pinilidine 103 I3796B2 (prednylidene), rimexolone, tixocortol, triamcinolone, propyl Triamcinolone acetonide, triamcinolone benetonide and triamcinolone hexacetonide 8. The pharmaceutical formulation according to claim 7, wherein the active drug is one or more steroid anti-inflammatory agents selected from the group consisting of cortisone and dexamethasone. ), hydrocortisone, methylprednisolone, prednisolone, prednisone, and fluocyanine. 9. The pharmaceutical formulation according to claim 6, wherein the active drug is one or more steroid anti-inflammatory agents selected from the group consisting of: naproxin, difenfen acid (diclofenac), celecoxib, rofecoxib, sulendac, diflunisal, piroxicam, indomethacin , etodolac, meloxicam, ibuprofin, ketoprofin, τ-flurbiprofen, per fen Mene and ethyl esters of mefenamic, nabumetone, tolmetin, aspirin and aspirin. 104 1379682 The pharmaceutical formulation according to claim 6, wherein the active drug is one or more anti-infective agents selected from the group consisting of: 2,4-diyl chimes (2,4) -diaminopyrimidines), for example, brodimoprim 'tetroxoprim, oxime benzyl; nitro. The class 0^ is for example. The husband tastes his copper (furaltadone). Furazolium chloride 'nifuradene, nifuratel, nifurfoline, nifurpirinol, nitrile Nifurprazine), nifurtoinol, nitrofuirantoin; quinolones and their analogues, such as cinoxacin, sepfenoxacin Ciprofloxacin), clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin ), lomefloxac丨η, miloxacin, nadifloxacin, naidixic acid, novesarsin, aufsin, oxaso Lin 酸 (〇x〇linic acid), pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rososocin Rosoxacin), rufloxacin, sparfloxacin, temafloxacin Oxacin, tosufloxacin, travosin; continuation of amines, such as acetonitrile, methoxy sulfamethoxypyrazine, benzylsulfamide, amiamine -b (chloramine-b), nitroamine-t 105 1379682 (chloramine-t), dichloramine t, η2-曱 曱 续 续 续 胺 ° ° ° °: (n2-formylsulfisomidine), N4-;S-d-glucosamine nitrite (η 4 -/5 - d - g 1 uc 〇 sy 1 su 1 fani 1 amide) gonadolide (mfenide), 4'- (methylamine continued (4f-(methylsulfamoyl)su lfanilanilide), noprylsulfamide, phthalyl sulfacetamide, phthalylsulfathi azole, willow Sulazosulfadimidine, amber oxime (succinylsulfathiazole), sulfabenzamide, reductive amine, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, hydrazine Sulfadiazine), sulfadicramide, sulfadimethoxine, sulfadoxine, and reductive amine. Sputa (sulfaethidole), sulfaguanidine, sulphate dimethyl 0δ sulfaguanol ' s sulfalene, sulfaloxic acid ' sulfamerazine sulfamerazine ), the amine is a sulfameter, a dimethylamine. ^ sulfamethazine, sulfamethizole, sulfamethomidine, sulphate, sulfamethoxypyridazine, sulfametrole ), sulfamidochrysoidine, sulfamoxole, benzenesulfonamide, 4-sulfanilamidosalicylic acid, η4-p-aminobenzene Benzene continued 106 1379682 N4-sulfanilylsulfanilamide, p-aminobenzene (8111 [311丨1丫11^63),! 1-N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, and allylic benzene Sulfaphenazole, sulfaproxyline, sulfapyrazine, ore. Sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, Sulfisomidine, sulfisoxazole; sulfones, such as acedapsone, acediasulfone, acetosulfone Sodium), dapresin, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid P-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone; others such as clofoctol, hexedine, and hexa Methenamine 'methenamine anhydromethylene-citrate, methenamine hippurate, hexamethylenetetramine phenylglycolate Salt (methenamine man) Delate), methimamine subsalicylate, nitroxoline, taurolidine, xibomol. 107 1379682 11. The pharmaceutical according to item 8 of the patent application for treating an inflammatory condition of an eye. 12. The pharmaceutical formulation of claim 11 further comprising ciprofloxin. The pharmaceutical according to claim 1, wherein the pharmaceutical formulation is implanted, and wherein the ocular disease is selected from the group consisting of the following: an iris neovascularization effect, a central visual network Edema, cell transplantation, cystic macular edema, edema, diabetic vaginal macular edema, pre-tuberculous vitreoretinopathy, proliferative diabetic retina; extensive exudative retinal detachment, diabetic retinal macular edema, deficiency Bloody eye disease, chronic focal reaction (chronic focal immunalogic comeal angiogenic glaucoma, flat vitrectomy, flat vitrectomy for retinopathy, uveitis, chronic uveitis, intraocular infections such as intraocular inflammation. The pharmaceutical formulation as described in claim 2, the pharmaceutical formulation, wherein the pharmaceutical formulation, the pharmaceutical formulation, a group of patients in need of treatment: a macula ocular cyst vaginal plaque blocked by a cataract vein Low intraocular pressure, proliferative glass writing, macular degeneration, edema, diffuse diabetes Corneal transplant graft reaction), a new, glass for proliferative sympathetic ophthalmia, intermediate, Irvine-Gass integrated formulation, wherein the formulation 1081379682 20% to 60% of the biocompatible and biodegradable adjuvant is 99.9% of the biocompatible and biodegradable adjuvant. 15. The pharmaceutical formulation of claim 2, which is in an injectable liquid or colloidal form, the formulation comprising 30% to the biocompatible and biodegradable adjuvant. a pharmaceutical formulation for sustained release of an active drug, a biocompatible and biodegradable adjuvant and at least one active drug or a salt thereof, wherein the formulation can be implanted by injection into the eye. The biocompatible and biodegradable adjuvant is selected from the group consisting of α, yS, γ and <5-tocopherol dextrorotatory, levorotatory and dextrorotatory and tocopherol esters, tocopherol esters a linear or branched aliphatic maleate selected from the group consisting of formate esters, propionates, C4 to C2G, malonic esters, fumarates, ascorbic acid esters and tobacco Alkali acid esters; a, β, γ and (the dextrorotatory, levorotatory and dextrorotatory and levorotatory isomers of the enol and the tocoisol, the ester of the tocotrienol is selected from the group consisting of formate, acetate ester , C 4 to C 2 〇 linear or branched fatty acid esters, cis, malonic esters, fumarates, succinates and nicotinic acid esters; benzene a carboxylic acid ester; dimethyl hydrazine; an ester and a triester formed with i citric acid and a linear or branched fatty alcohol of <:1 to C1G; or 30% to the formula 99. 9% of the pharmacy is included in the pharmacy; and the group consisting of levorotatory esters, acetates, succinic acid 5-tocotrienols, propionate diesters, ascorbic f (9-Ethyl monoester, double 109 1379682 * wherein the ratio of the adjuvant is at least 2% of the formulation; wherein the adjuvant provides sustained release of the active drug; wherein the formulation does not comprise a polymer or surfactant And the zero-order kinetics in which the active drug released from the formulation exhibits a period of at least one week. 110