WO2008033910A2

WO2008033910A2 - Punctum: drug delivery site for therapeutic peptides and proteins

Info

Publication number: WO2008033910A2
Application number: PCT/US2007/078256
Authority: WO
Inventors: Josefino B. Tunac; Jaime V. Aragones
Original assignee: Tunac Josefino B; Aragones Jaime V
Priority date: 2006-09-12
Filing date: 2007-09-12
Publication date: 2008-03-20
Also published as: WO2008033910A3

Abstract

Disclosed is an. alternate route for drug delivery, which involves the punctum. The lacrimal punctum is an opening in the corner of the eye through which tears drain into the nasolacrimal duct, a highly vascularized collection system. Delivering therapeutic peptides or proteins into the punctum allows the drug to 'be naturally absorbed into the lacrimal vascularization for systemic distribution into the bloodstream. Since the punctum is a natural opening, this would constitute a painless route for drag administration. In one embodiment, SOD is introduced into the punctum and absorbed intact into the blood stream without antigenic or unwanted allergic reaction. The drug absorption site could start in the punctum and continue on to the canaliculi, lacrimal sac, ami nasolacrimal drainage system, to the nasal meatus. Also, diffusion to the highly vascularized choroids may occur due to proximity oi'the punctum to ihti lacrimal lake.

Description

PUNCTUM: DRUG DELIVERY SITE FOR THERAPEUTIC PEPTIDES AND PROTEINS

BACKGROUND

[0001] The development of recombinant DNA and monoclonal antibody technologies in the 1970s marked a new era in biotechnology involving genetic engineering. Thus, recombinant DNA (rDNA) technology, cell fusion, or processes involving genetic manipulation allowed the production of complex peptides and proteins. The first drug produced via genetic engineering was human insulin, which was marketed in 1982. By mid-2000, 84 rDNA products were approved for marketing; currently there are 600 to 700 peptide and protein-based therapeutics in development worldwide. In 1999, there were 369 biotechnology drugs in US clinical development against 438 disease indications and 13% of new medicines approved by the FDA in the 1990s; they account for six of the top 50 selling drugs. The list of human health conditions for which the FDA has approved rDNA drugs includes AIDS, anemia, certain cancers (Kaposi's sarcoma, leukemia, and colorectal, kidney, and ovarian cancers), certain circulatory problems, certain hereditary disorders (cystic fibrosis, familial hypercholesterolemia, Gaucher's disease, hemophilia A, severe combined immunodeficiency disease, and Turner's syndrome), diabetic foot ulcers, diphtheria, genital warts, hepatitis B, hepatitis C, human growth hormone deficiency, and multiple sclerosis.

[0002] Some of the notable biotech drugs that are currently marketed include: Activase

(for breaking blood clots), Herceptin (breast cancer), Rituxan (Non-Hodgkin's lymphoma), Neutropin, and Humatrope (growth hormone deficiency), Xolair (allergic asthma), Raptiva, and Amevive (psoriasis), Epogen, and Procrit (for anemia), Neupogen (white cell growth promoter), Enbrel. Humira, and Remicade (rheumatoid arthritis), Avonex, and Betaseron (multiple sclerosis), Intron A (anticancer/antiviral), Recombivax (hepatitis B), Proleukin (cancer), Regranex (diabetic foot ulcer), Synagis (respiratory synctial virus infection in infants), Flumist (flu vaccine), Humulin (type I diabetes), Reopro (anti-clotting), Xigris (sepsis), and Forteo (osteoporosis).

[0003] Typical of complex molecules, the above compounds are administered by subcutaneous, intravenous, or intramuscular injection. When these compounds are administered by oral route, they are likely to be poorly adsorbed, denatured in the digestive system, acid- hydrolyzed in the stomach, enzymatically degraded (proteolysis) by endo/exo-peptidases, and filtered out by the kidneys very quickly. Such drugs are best administered by injection; however, they may elicit antigenic (eliminated by B and T cells) and unwanted allergic reactions, or even toxicity. If they were to be delivered orally, they must be formulated to protect them from the hostile GI environment, e.g., coadministration with nonspecific protease inhibitors or chemical modifications for improved resistance to enzymatic degradation.

[0004] Since injection is associated with certain degree of pain, several non-invasive techniques have been offered for peptides and proteins. These include transdermal patch and mucosal routes (buccal, pulmonary, nasal, rectal, vaginal) with varying degrees of success. However, the skin is a formidable barrier to overcome for transdermal drug delivery to be effective. The skin protects the body very effectively and generally is only permeable to small, lipophilic drugs. Mucosal routes have been used successfully for the delivery of low-molecular weight drugs. However, a number of problems have to be addressed including molecular size, solubility, chemical stability, hydrophilic character and charge/dissociation, which are associated with poor absorption and low bioavailability.

[0005] Drug administration by an ocular route has been proposed as well, e.g., for topical medications on the eye (U.S. Pat. No. 3,826,258; U.S. Pat. No. 4,923,699); sustained release systems placed into the conjunctival cul-de-sac, between the lower lid and the eye (U.S. Pat. No. 3,618,604; U.S. Pat. No. 3,626,940; U.S. Pat. No. 3,845,770; U.S. Pat. No. 3,962,414; U.S. Pat. No. 3,993,071 ; U.S. Pat. 5,731 ,005; and, U.S. Pat. No. 4,014,335); for injections to the vitreal cavity (U.S. Pat. 5,725,493); or even associated with the use of ophthalmic insert for sustained release of medication to the eye (U. S. Pat 6,196,993). This last patent describes a collarette equipped with reservoir for controlled release of medication to be inserted into the lacrimal punctum for the treatment of local eye infections including inflammation, glaucoma, and other ocular diseases; it does not claim systemic drug delivery throughout the body. [0006] Thus, there is a need to devise an effective delivery system for large molecules such as peptides and protein therapeutics, for systemic drug distribution throughout the body. Particularly needed is a non-invasive route to deliver quantitative drug dosages without the associated antigenic or allergenic reactions. One non-limiting example of a therapeutic large molecule is superoxide dismutase. Superoxide dismutase (SOD) is an antioxidant enzyme with a molecular weight of 32,000, which catalyzes or neutralizes the harmful effects of superoxide or free radicals. In this regard SOD has been evaluated as an anti-inflammatoiy/antiarthritic compound but it is degraded when administered orally. On the other hand, injection is impractical and ineffective because of a short half-life in the bloodstream: 50% is neutralized in 5 min. Moreover, in clinical trials, injection of SOD has produced anaphylaxis reactions (J Investig Allergol Clin Immunol. 1993 Mar-Apr;3(2): 103-4; Allergol Immunopathol (Madr). 1990 Sep- Oct;18(5):297-9). [0007] Because of their large molecular weight, therapeutic proteins are unable to cross the cell membrane, as they are highly hydrophilic. For this reason liposomes have been investigated as SOD carriers. When entrapped in liposomes, SOD proved to be effective against several inflammatory indications (i.e., rheumatoid arthritis, ischemia, and liver necrosis). However, SOD liposomes lack stability and the ability to ensure long-term sustained release. This problem was addressed by creating polymeric microspheres (MS), which showed potential for long-term sustained release of the enzyme for the treatment of inflammatory diseases including rheumatoid arthritis or other intra-articular and joint diseases. (AAPS PharmSciTech. 2004; 5(4): article 51).

SUMMARY

[0008] Disclosed herein is a method for delivering at least one bioactive material into systemic uptake in which the method includes the step of introducing a bioactive material into contact with the nasolacrimal system of a patient for an interval sufficient to achieve systemic uptake of a quantity of the bioactive material.

DESCRIPTION OF THE DRAWINGS

[0009] Reference is made to the following drawing figures in which:

[0010] Fig. 1 is a schematic depiction of the anatomy of the nasolacrimal drainage system;

[0011] Fig. 2 is a detail of a portion of the nasolacrimal drainage system with typical dimensions for humans noted.

DETAILED DISCRIPTION

[0012] Disclosed herein is a method for drug delivery that utilizes the nasolacrimal system as a non-invasive and effective delivery route for various therapeutic agents; particularly for therapeutic agents involving large molecules including, but not limited to, SOD. It is contemplated that the therapeutic agent can be delivered into the blood stream via the punctum with little or no observed allergenic or antigenic reactions.

A. Drug Delivery.

[0013] The active ingredient in a medicine is only part of the arsenal against disease. The drug must be delivered to the right place at the right time and amount that assures the desired pharmacological effect. The medication is expected to circulate through the whole body reaching the cells and organs that are dysfunctional as well as those that are healthy. For drugs that clear rapidly from the body, achieving and maintaining the drug concentration within the therapeutic window requires a multiple dosing regimen, often more than once a day. This dosing regimen can lead to a lack of patient compliance as well as fluctuation in drug levels in the plasma. Typical drug formulations provide prompt release of drug in a bolus form. However, drugs could be formulated to control and sustain the rate of delivery over the duration of therapeutic activity, or target the delivery of drug to a tissue or organ. Controlled drug delivery can be achieved in various forms, e.g., hydrogels, nanoparticles, microparticles, transdermal, etc. [0014] Drugs can be delivered by oral ingestion or via injection for systemic distribution throughout the body. Oral dosage forms can be solids, liquids (homogenous and heterogeneous systems), semisolids, and aerosols. Solid dosage forms include different types of compressed tablets, granules, troches, lozenges, coated dosage forms, and hard and soft gelatin capsules. Liquid dosage forms include solutions, suspensions, emulsions, and buccal and sublingual sprays. Topical dosage forms are applied to the skin and include ointments, pastes, creams, lotions, liniments, and transdermal patches. Some dosage forms are formulated for application to body cavities, e.g., rectal and urethral suppositories and vaginal pessaries. Inhalation aerosols, using metered dose inhalers (MDIs), dry powder inhalers (DPIs) and nebulizers, are used to deliver drugs to the respiratory tract. Nasal route administration uses solution and suspension dosage forms.

[0015] Drugs made up of small molecules can be administered by oral route since they are permeable and absorbed from the intestines. On the other hand, large molecule drugs that are peptide or protein in nature are difficult to deliver by oral administration. Such protein or peptide based therapeutics are poorly adsorbed, subject to denaturation in the digestive system, acid hydrolysis in the stomach, enzymatic degradation (proteolysis) by endo/exo-peptidases, and filtered out by the kidneys very quickly. Moreover, proteinaceus drugs are antigenic (eliminated by B and T cells) and unwanted allergic reactions may develop, even toxicity. Thus, for oral delivery, peptide and protein drugs must be formulated to protect them from the hostile GI environment, e.g., coadministration with nonspecific protease inhibitors or chemical modifications for improved resistance to enzymatic degradation.

[0016] The most effective delivery route for therapeutic protein is by injection. However, formulations must be sterile and injections, by their very nature, are inevitably associated with some degree of pain, irrespective of their route of delivery, whether intramuscular, intravenous, or subcutaneous. This results in poor patient compliance. Indeed, a painless and effective drug delivery system would be ideal.

[0017] Alternative painless delivery systems are available for certain drug delivery applications. These include noninvasive transdermal delivery routes and/or mucosal tissue delivery routes. The transdermal delivery route is particularly applicable to potent lipophilic compounds. However, transdermal and/or mucosal delivery systems do not provide rapid elevation in therapeutic blood levels. Transdermal routes include, but are not limited to, the mucosal route. Mucosal delivery sites include nasal mucosal tissue, as well as tissue in the pulmonary, rectal, vaginal, buccal, and sublingual regions. For the delivery of peptides and proteins, the nasal cavity can be advantageously employed, followed by the vaginal route, pulmonary route, oral route, and transdermal route. Ocular delivery routes are not typically utilized for delivery of large protein and peptide compounds.

Parenteral (Injection):

[0018] Drug delivery for various therapeutic agents can be accomplished by parenteral methods. Various forms of injection introduction include, but are not limited to, intravenous, intramuscular, subcutaneous, intradermal delivery methods. This is the preferred delivery route for most proteins in that it allows rapid and complete absorption, allows smaller dose size (less waste), and avoids first pass metabolism. On the other hand, there could be problems with overdosing (necrosis), tissue reactions/hypersensitivity, and pain.

[0019] The United States Pharmacopoeia 24 defines a small-volume injectable (SVI) as

"an injection that is packaged in containers labeled as containing 100 ml or less." Therefore, all sterile products packaged in vials, ampules, syringes, cartridges, bottles, or any other container that is 100 ml or less fall under this classification. Ophthalmic products packaged in squeezable plastic containers, although topically applied to the eye rather than administered by injection, also fall under the classification of small-volume injections as long as the container size is 100 ml or less. Large-volume injectables (LVI) have to be terminally sterilized, whereas SVIs can be sterilized terminally or by aseptic filtration and processing. In fact, 80% or greater of all SVIs commercially available are prepared by aseptic processing. LVIs usually involve intravenous infusion, dialysis, or irrigation fluids containing electrolytes, sugar, amino acids, blood, blood products, and fatty lipid emulsions. LVIs must be administered by intravenous administration. Small-volume injections may be injected by intravenous, subcutaneous, or intramuscular routes (primary routes of parenteral administration) or by various secondary routes such as intraabdominal, intra-arterial, intra-articular, intracardiac, intracisternal, intradermal, intraocular, intrapleural, intrathecal, intrauterine, or intraventricular injections. SVI formulations are relatively simple, composed of the active ingredient, a solvent system (preferably aqueous), a minimal number of excipients, and the appropriate container and closure packaging system. If the active ingredient is unstable in solution or suspension, the product can be a dry powder, processed either by lyophilization or by sterile crystallization. Non-parenteral/non-invasive

1. Peroral (Oral)

[0020] A drug can be administered via many different routes to produce a systemic pharmacologic effect. The most common method of drug administration is via the peroral route, in which the drug is swallowed and enters the systemic circulation primarily through the membranes of the small intestine. Although this type of drug administration is commonly termed oral, peroral is a better term because oral administration more accurately describes drug absorption from the mouth itself. Peroral administration is the easiest and most convenient drug delivery method; it is a desirable method of administering therapeutic agents for their systemic effects mainly because of patient acceptance, convenience in administration, and availability of cost-effective manufacturing processes. However, for proteins and other macromolecules, the oral delivery route is difficult to accomplish. The first challenge is simply getting the molecule past the digestive system and avoiding degradation. Other challenges include the inherent physicochemical nature of the drugs and/or the variability in gastrointestinal (GI) conditions. Variability in GI conditions can include, but is not limited to, factors such as pH, presence of food, transit times, expression of P-Glycoprotein(P-Gp) and CYP3A, as well as enzymatic activity in the alimentary canal. Manipulation of these problems and challenges is considered an important strategy for improving oral drug delivery, and requires thorough understanding and appropriate integration of physicochemical principles, GI physiology and biochemistry, polymer science, pharmacokinetics, and pharmacodynamics.

[0021] Drugs with limited potential for oral delivery include, but need not be limited to, those that are poorly absorbed in the upper gastrointestinal (GI) tract and unstable to proteolytic enzymes; as well as drugs that cause local stomach or upper GI irritation or require doses in excess of 500 mg. Limitations on oral drug delivery also can occur in various patient populations, notably children, the elderly, and those with swallowing problems. Oral drug delivery systems (DDS) can be classified into three categories: immediate-release (IR) preparations, controlled-release (CR) preparations, and targeted-release preparations.

2. Transdermal patch

[0022] Trandermal drug delivery is based on the absorption of drug into the skin after topical application. In contrast to orally delivered drugs, compounds entering the body through the skin escape first-pass metabolism in the liver. This can often result in higher bioavailability. In addition, transdermal delivery can be used to deliver drugs to nauseous patients. Trandermally delivered therapeutic agents are little affected by intake of food, and can be easily interrupted. In contrast to injection, transdermal administration is noninvasive and poses little risk of infection. It is also relatively easy for patients to apply and remove a transdermal system. Because transdermal drug delivery allows continuous delivery of drugs, frequent bolus dosing of drugs with short half lives is avoided. As a result, the side effects, or variability in therapeutic effect due to peaks and troughs in plasma concentration, that are seen with bolus administration are minimized.

[0023] Transdermal drug delivery, however, involves the inherent challenge of overcoming the skin barrier. Skin protects the body from the environment very effectively and generally is only permeable to small, lipophilic drugs. Transdermal delivery systems, therefore, not only have to provide the desired drug/therapeutic agent to the skin under stable conditions and in a format convenient to the patient, but also serve to locally increase the permeability of skin to larger, charged, or hydrophilic drug molecules while minimizing irritation. [0024] Several different strategies have been explored to increase permeability of the skin. Permeability can be modified by chemical additives, use of an electric field to drive charged molecule across the skin, or mechanical creation of microscopic transport channels through the skin. Although it is generally accepted that, for most drugs, the stratum corneum (SC) is the rate- limiting barrier to drug permeation, differences in drug permeation at different anatomical sites are unlikely to be just a function of the SC. Site-to-site differences may arise because of differences in the rate and amount of drugs being delivered, drug permeation into and across the skin, and drug clearance from the skin.

3. Mucosal

[0025] Drugs are absorbed across mucosal membranes from various absorption sites, such as nasal, buccal/sublingual and rectal regions. These sites offer some advantages for systemic drug delivery as compared with the peroral route, which could include liver bypass, faster onset drug action and avoidance of gastrointestinal metabolism. [0026] These mucosal routes have been used successfully for the delivery of low- molecular weight drugs. However, problems are still associated with the delivery of high molecular weight drugs, particularly peptides and proteins. Most notable are molecular size, solubility, chemical stability, hydrophilic character and charge/dissociation resulting in poor absorption and low bioavailability. Also there are physiological barriers including pH of the milieu; texture of the membrane; available absorptive surface area; permeability; and the proteolytic enzymes present in and around the mucosal flora. Since physiological barriers cannot be changed, adding excipients to the formulation, camouflaging the molecule with polymeric materials, or modifying the drug structure are being evaluated. Buccal/Sublingual Route

[0027] The surface area available for absorption in the buccal mucosa is much smaller and less permeable than the gastrointestinal, nasal, rectal, and vaginal mucosae. The buccal mucosa is continuously bathed by saliva, and the secreted saliva lowers the drug concentration at the absorbing membrane. Moreover, involuntary swallowing of saliva containing dissolved drug, as well as activities such as talking, eating, and drinking affect the retention of the delivery system. Taste, irritancy, and allergenicity also may limit the number of drugs that can be delivered by the buccal route.

Nasal route.

[0028] About 2% of the overall drug delivery is administered via the nasal route. The most popular type of nasal drug delivery is the administration of locally acting products including decongestants or anti-inflammatory drugs to treat rhinitis or allergy-related indications. The nasal route can be a viable alternative to parenteral administrations, providing direct access to systemic circulation and a rapid onset of action. Application of drugs or pharmacologically active compounds via intranasal route dates back to the beginning of human civilization, e.g., ayuverdic medicine, sniffing tobacco or hallucinogens.

[0029] The nasal cavity is easily accessible, extensively vascularised and highly permeable. Compounds administered via the nasal route are absorbed directly into the systemic circulation, avoiding the hepatic first-pass effect. The peptide oxytocin, which stimulates uterine contraction and lactation, was one of the first nasally administered peptide hormones. [0030] There are a number of factors that limit the widespread utility of the nasal delivery route for many peptides and proteins. These include, but are not limited to, rapid mucociliary clearance; enzymatic degradation in the mucus layer and the nasal epithelium; low permeability of the nasal epithelium; and, the physico-chemical properties of the delivered compound. Bioavailabilities tend to be significantly lower than parenteral administration, particularly for compounds whose molecular weight is greater than 1,000.

[0031] Factors that enhance nasal absorption may include the reduction in mucociliary clearance, increase in the transepithelial transport of the compounds and minimized metabolism. These could be achieved by the use of permeation enhancers and bioadhesives including bile salts, dihydrofusidates, surfactants and fatty acid derivatives. For example chitosan, a bioadhesive polymer, improves absorption by increasing the contact time between the drug and the nasal membrane. Other bioadhesive materials include materials such as carbophil, cellulose agents, gelatin microspheres, cyclodextrin, starch and dextran. b. Pulmonary Route

[0032] The lungs provide a route for rapid absorption of compounds or materials into the bloodstream, sometimes even faster than subcutaneous injections. The total surface area of the lung is about the size of a tennis court in a normal adult and can be accessed in a single inhalation. Although drug absorption in the lungs is rapid, it tends to be less efficient than injections. For example, the bioavailability of inhaled insulin is somewhere between 10 and 15% of what it would be if it were administered as an injection. For larger molecules, the body clears such molecules from the lungs by several mechanisms, including metabolism and phagocytosis (uptake by white cells known as phagocytes).

[0033] Also, the efficiency of pulmonary delivery depends greatly on coordination of the patient's breathing cycle with the actuation of the drug delivery device. For example, aerosols leave traditional inhalers so quickly that much of the medicine cannot negotiate the bends of the airway and ends up driven into the back of the throat.

c. Vaginal Route.

[0034] The vaginal route may serve as a novel site for drug delivery for therapeutic proteins and peptides. This route enables direct entry into the blood stream with the possibility of bypassing the hepatic-gastrointestinal metabolism. Orally administered drugs that are metabolized extensively, such as progesterone and estrogen, have been delivered intravaginally for achieving their systemic activity.

[0035] Pharmaceutical dosage forms available for intravaginal delivery consist primarily of those used to treat a specific gynecological condition. Products available include vaginal contraceptives, antifungals, antimicrobials, cleansers, deodorants, and lubricants. These products are formulated as tablets, capsules, creams, suppositories, foams, films, solutions, ointments, and gels.

d. Rectal Route

[0036] Rectal drug administration is amenable to both local and systemic drug delivery. It has been effectively utilized to treat local diseases of the anorectal area as well as to deliver drugs systemically as an alternative to oral administration. Although rectal drug administration is unlikely to ever become a commonly accepted route of administration, the utilization of this technology for particular applications and therapeutic problems offers an alternative delivery route, which can be successfully applied in drug therapy.

[0037] Solid suppositories are the most common dosage form used for rectal drug administration and represent greater than 98% of all rectal dosage forms. Typically, these are torpedo-shaped dosage forms composed of fatty bases (low-melting) or water-soluble bases (dissolving), which vary in weight from 1 g (children) to 2.5 g (adult). Lipophilic drugs are usually incorporated into water-soluble bases while hydrophilic drugs are formulated into the fatty base suppositories.

[0038] Solutions, suspensions, or retention enemas represent rectal dosage forms with very limited application, largely due to inconvenience of use and poor patient compliance. In many cases, these formulations are utilized to administer contrast media and imaging agents for lower GI roentgenography. Although drug absorption from solutions has been shown to exceed that from solid suppositories in some cases, this particular administration route is only infrequently employed. The use of gels, foams or ointments for rectal administration can afford advantages over liquid formulations because retention of the dosage form in the rectal cavity reduces patient compliance problems. Drug release with semisolid dosage forms is usually limited to local indications such as hemorrhoids and lower bowel inflammation (proctitis). Drug release and subsequent pharmacologic action is usually faster with semisolid formulations than with solid suppositories since a lag time is not required for melting or dissolution. [0039] The feasibility and effectiveness of this route has been examined for the delivery of peptides and proteins. The main advantages of the rectal mucosal membrane are its thickness and vascularity in comparison with the colon. Another reason for preferring this route is that when drugs are delivered rectally, the liver can perhaps be avoided to some extent. Historically, the rectum also has fewer amounts of degradative enzymes in comparison with other traditional delivery routes.

[0040] However, one of the main problems with this route is patient acceptance.

Lipophilic or hydrophilic based rectal suppositories can be formulated. These bases would help in improving the bioavailability of water-soluble compounds along with other incorporated absorption promoters and enzyme inhibitors. The rectal delivery route still lacks any significant progress or major breakthrough with regard to its application in humans.

e. Oral mucosa

[0041] Unique features of the oral mucosa that can hasten absorption of molecules include the abundant vascularization, rapid recovery time after exposure to stress and the near complete absence of Langerhans cells. The absence of Langerhans cells is especially significant because, this can make the oral mucosa relatively tolerant to potential allergens. Another very significant advantage of using the oral transmucosal route for drug delivery is that this route can effectively bypass first pass lower metabolismand thus avoid the pre-systemic elimination seen with the gastrointestinal tract. There is minimal proteolytic activity and this avoids the problems of enzymatic degradation of peptide and protein drugs. However, a constant flow of saliva and a multi-layered epithelium constitute an effective barrier for drug absorption. [0042] Three main sites in the oral cavity where drug delivery can be effected are: the sublingual region (lining the floor of the mouth); the buccal region (lining the cheeks, buccal mucosa); and the oral cavity where direct delivery can be effected. The epithelium of the buccal mucosa is about 40-50 cell layers thick, while the sublingual epithelium has a slightly lesser number of cells and is more permeable than the buccal mucosa. However, the sublingual mucosa lacks the rich density of smooth muscle fibers needed for efficient transmucosal delivery system. Also, the constant downward flow of saliva within the oral cavity makes difficult to retain drugs in the sublingual mucosa for absorption.

[0043] Thus, the buccal mucosa is more suited than sublingual for sustained delivery applications, delivery of less permeable molecules, and even peptide drugs. The permeability of the buccal mucosa is 4 to 4000 times greater than that of the skin It has an advantage over injectable routes in that it is user-friendly and non-invasive. It is advantageous over peroral routes in that the drug is not subjected to the destructive acidic environment of the stomach and therapeutic serum concentrations of the drug can be achieved more rapidly. [0044] In general, drugs penetrate the mucous membrane by simple diffusion and are carried in the blood, which richly supplies the salivary glands and their ducts, and into the systemic circulation via the jugular vein. Active transport, pinocytosis, and passage through aqueous pores usually play only insignificant roles in moving drugs across the oral mucosa. Two sites within the buccal cavity have been used for drug administration. Using the sublingual route, as for glyceryl trinitrate (GTN), the medicament is placed under the tongue, usually in the foπn of a rapidly dissolving tablet. The second anatomic site for drug administration is between the cheek and gingiva.

f. Ocular

[0045] Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the major causes of blindness. Glaucoma, posterior uveitis and retinitis also contribute considerably to loss of vision. These conditions affect tissues at the back of the eye, where drug treatment is difficult to administer. AMD and DR are conditions caused by angiogenesis (blood vessel growth), resulting in unwanted neovascularization that damages the retina. There are many existing and novel pharmaceutical products with the potential pharmacology to treat retinal diseases; however, the complexity of the human eye presents unique challenges for drug delivery. [0046] Current methods for ocular delivery of therapeutic agents include topical administration (eye drops), subconjunctival injections, periocular injections, intravitreal injections, surgical implants, and systemic routes. However, all of these methods have limitations. Therapeutic levels of many drugs are difficult to achieve in ocular tissues and systemic toxicities are of concern when oral and intravenous routes of administration are used. Intravitreal injections, periocular injections, and sustained-release implants can be used to achieve therapeutic levels of drugs in ocular tissues, but invasive methods are inherently risky due to the potential for bleeding, infection, retinal detachment, and other local injuries. [0047] Eye drops are useful in treating conditions affecting either the exterior surface of the eye or tissues in the front of the eye, but cannot penetrate to the back of the eye for treatment of retinal diseases. One technique being developed is an ocular iontophoresis system, which delivers drugs safely and noninvasively to the back of the eye. Iontophoresis uses a small electrical current to transport ionized drugs into and through body tissues. [0048] The modified mucosal surface that covers the cornea is a significant barrier to topically applied eye drop medications. The tight junctions between the basal epithelial cells of the cornea and the tear fluid drainage causes less than 5% of topically applied drug to permeate the cornea and reach intraocular tissues. As a result, drugs delivered with eye drop formulations are generally limited to treating tissues in the front of the eye. Examples include topical antimicrobials used to treat bacterial conjunctivitis or ocular antihypertensive drops that function by reducing the aqueous humor production at the level of the ciliary body (located in the front of the eye) to treat glaucoma. An attempt to deliver drugs to the posterior structures of the eye with systemic medications is impeded by the blood-retinal-barrier, which consists of the tight junctional complexes of the retinal pigment epithelium and retinal capillaries. This barrier reduces the penetration of most drugs given systemically to the posterior segment of the eye and hinders the treatment of many retinal diseases. Although high doses of systemically administered medications may be able to penetrate the blood-retinal-barrier and provide therapeutic drug levels to the back of the eye, serious systemic side effects may occur.

[0049] Delivery of drugs directly into the eye by intravitreal injection through the pars plana is another approach to achieve therapeutic levels of drug to treat retinal diseases. However, given the short half-life of most drugs injected into the vitreous, frequent injections 1-3 times per week are required to maintain therapeutic drug levels. As a result, intravitreal drug injections are very useful in treating acute bacterial infections of the eye (i.e., endophthalmitis) that may require one or two injections, but are not well tolerated by patients that may require months or years of injections to treat chronic eye diseases such as AMD or cytomegalovirus (CMV) retinitis. Furthermore, frequent injections increase the risk of retinal detachment, vitreous hemorrhage, endophthalmitis, and cataracts.

[0050] The nasolacrimal drainage system serves as a conduit for tear flow from the external eye to the nasal cavity. This system, as shown in Fig. 1, consists of the puncta 10, common 20, inferior 40 and superior 30 canaliculi, lacrimal sac 50, and nasolacrimal duct 60. Puncta 10 are openings (0.3 mm in diameter) are located on the medial aspect of the upper and lower eyelid margins. Each punctum sits on top of an elevated mound known as the papilla lacrimalis. The inferior punctum is approximately 0.5 mm lateral to the superior punctum, with distances to the medial canthus of approximately 6.5 mm and 6.0 mm respectively. Tears within the medial canthal area enter the puncta to pass into the canaliculi. [0051] Canaliculi have an initial vertical segment measuring approximately 2 mm followed by an approximately 8 mm horizontal segment. The angle between the vertical and horizontal segments is approximately 90 degrees, and the canaliculi dilate at the junction to form the ampulla. The horizontal portion of the canaliculi converges to form the common canaliculus 20. Canaliculi pierce the lacrimal fascia before entering the lacrimal sac 50. At its entrance to the lacrimal sac 50, the common canaliculus 20 may dilate slightly, forming the sinus of Maier. [0052] Canaliculi are lined by nonkeratinized-stratified squamous epithelium and are surrounded by elastic tissue, which permits dilation to approximately 2 or 3 times the normal diameter. The oblique entrance of the common canaliculus into the lacrimal sac forms the valve of Rosenmϋller 70, which prevents retrograde reflux of fluid from the sac into the canaliculi. However, the posterior angulations of the upper and lower canaliculi 30, 40 followed by anterior angulations of the common canaliculus 20 may also block reflux at the canaliculus-sac junction. An incompetent valve of Rosenmϋller 70 is observed clinically as air escaping from the lacrimal puncta when the individual blows his or her nose.

[0053] Discussed herein is a method for administering a systemic bioactive material utilizing the nasolacrimal system of a mammal. The method disclosed herein is based, at least in part, on the discovery that various bioactive materials such as peptides, proteins, and various bulky molecules can be efficiently and effectively administered to achieve therapeutic levels in the bloodstream of a patient by introduction through at least one puncture of the patient. The method disclosed herein contemplates introducing at least one bioactive material suitable for systemic uptake through the nasolacrimal system into contact with at least one punctum. The method can include the step of placement of at least one bioactive agent in the eye and exfiltration into the nasolacrimal system through at least one punctum. [0054] The introduced bioactive material resides in the lacrimal system for an interval sufficient to permit systemic uptake through at least one component of the lacrimal system and/or associated ducts, glands, and regions. Also, diffusion to the highly vascularized choroids may occur due to proximity of the punctum to the lacrimal lake.

[0055] As used herein, the term "nasolacrimal system" includes at least one punctum 10 located proximate to ocular tissue and serves as a conduit for tear flow from the external eye to the nasal cavity. As shown in Fig. 2, the nasolacrimal system can include various ducts, channels, sacs, etc., configured to convey drainage from eye to the nasal cavity. These include but need not be limited to ampula 80, 90 (superior and/or inferior), caniculosi (superior 30, inferior 40 and common 20) conveying fluid from the punctum 10 to a suitable collection point such as the lacrimal sac 50. The lacrimal sac 50 can discharge into a suitable duct such as the nasolacrimal duct 60. The nasolacrimal system may have various regions associated and proximate to the discharge of the nasolacrimal duct 60. Nonlimiting examples of such regions include the inferior concha 100 and inferior meatus 110. Also in that area are the maxilla bone 120 and the valve of Hasner 130.

[0056] "Bioactive agents" as the term is used herein is taken to mean materials that exhibit activity to interact with or act upon a biological target. Such materials can include various compounds such as peptides, proteins, bulky compounds, and complex molecules that are employed in processes including, but not limited to, various peptide and protein-based therapeutics useful in treatment of various conditions and disease indications. [0057] Bioactive agents may include pharmacologically active substances that produce a local or systemic effect in animals, preferably mammals or humans. The term may include substances used in the diagnosis, cure, mitigation, treatment, or prevention of disease or enhancement of desired physical or mental development and conditions in an animal or human. Nonlimiting examples of therapeutic bioactive agents include, but are not limited to general classes of compounds such as biologicals; recombinant therapeutics and synthetics. Non-limiting examples of biologicals are virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, and allergenic products. Non-limiting examples of recombinant therapeutics are hormones, growth factors, interferons, interleukins, insulin, enzymes, prostaglandins, granulocyte colony stimulating factors, granulocyte macrophage colony stimulating factor, and follicle stimulating hormone. The materials can be those used to combat infectious disease as well as materials such as cardiovasculars, diabetes, cancer, inflammatory disease, neurological disorders immunological disorders and the like. [0058] Non-limiting examples of therapeutic materials can include superoxide dismutase

(SOD) and other therapeutic enzymes including but not limited to streptokinase (Streptase®), asparaginase, rhDNAse (Pulmozyme®), tissue plasminogen activator (Activase), imiglucerase (Cerezyme®) non enzyme proteins into the punctum epoetin alfa (Procrit) or (Epogen); filgrastim (Neupogen); pegfilgrastim (Neulasta); insulin systemic (Novolin); interferon beta-la (Avonex); pegylated interferon alpha (PEG-Intron A franchise); etanercept (Enbrel); darbepoetin alfa (Aranesp); epoetin-beta (NeoRecormon) and somatotropin.

[0059] It is contemplated that the bioactive agent can be contained in a suitable device or compounded with suitable materials to facilitate uptake through the nasolacrimal system. In the process disclosed herein, it is contemplated that a device can be removably inserted into contact with the punctum of the patient. The device is configured to contain the bioactive agent. As employed herein, the term "into contact with the punctum" is taken to include insertion or introduction to or through the punctum. Such methods can include insertion of a suitable tube into the punctum as well as ejection of bioactive proximate to the punctum in a manner that facilitates uptake through the punctum. Where suitable this can include injection of bioactive agents proximate to the punctum in the region of the medial canthral in a manner that permits entrance into the nasolacrimal system through the punctum.

[0060] It is contemplated that the bioactive agent by provided in a kit for delivering bioactive materials through a punctum. The kit would comprise a device having an exit orifice configured to contact or enter a punctum at the appropriate location for delivery to the desired position for proper absorption into the bloodstream. The device will have at least one reservoir for containing a bioactive material of which various examples are described herein. The device will have means for delivering the bioactive material through the punctum by way of the exit orifice. The means may include for example squeezing the reservoir, injecting the material, etc. Il is contemplated that multiple reservoirs may be utilized in the device for mixing more than one biomaterial or a biomaterial and another compound, such as a rapid release compound. The materials may also be metered in another embodiment.

[0061] It is further contemplated that the device and or kit will contain jigs to assist in the positioning of the exit orifice of the device to assist in proper location of the exit orifice. Further, instructions may be included with the kit that describe proper administration, reuse, disposal, storage, refilling, or other necessary operation of the device.

[0062] It is contemplated that the bioactive agent or agents can be introduced to the punctum in the form of solids, liquids (homogenous and heterogeneous systems), semisolids, lyophils, or extracts. Solid dosages could be in the form of tablets, granules, troches, lozenges, coated dosage forms, and hard and soft gelatin capsules, ointments, pastes, creams, lotions, and liniments. Liquid dosage forms can include suitable solutions, suspensions, and emulsions. [0063] Bioactive materials or drugs introduced to the punctum can be compounded in pharmaceutical formulations that include formulations characterized as drugs introduced to the punctum in pharmaceutical formulations including conventional rapid-release, delayed-release and time controlled-release formulations,

[0064] It is contemplated that the bioactive agent or agents can be introduced to the punctum in the form of solids, liquids (homogenous and heterogeneous systems), semisolids, lyophils, or extracts. Solid dosages could be in the form of tablets, granules, troches, lozenges, coated dosage forms, and hard and soft gelatin capsules, ointments, pastes, creams, lotions, and liniments. Liquid dosage forms can include suitable solutions, suspensions, and emulsions. [0065] Biomaterials for controlled release may include, but are not limited to, poly(urethanes) for elasticity, poly(siloxanes) or silicones for insulating ability, poly(methyl methacrylate) for physical strength and transparency, poly(vinyl alcohol) for hydrophilicity and strength, poly(ethylene) for toughness and lack of swelling, poly(vinyl pyrrolidone) for suspension capabilities. Other materials include, but are not limited to, poly(2-hydroxy ethyl methacrylate). poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(methacrylic acid), polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolides) (PLGA), polyanhydrides, polyorthoesters. sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC).

[0066] It is also contemplated that the bioactive material can be formulated as nanoparticles that are introduced to the punctum using materials that include, but are not limited to poly(ethylene oxide)-poly(L-lactic acid)/poly(beta-benzyl-L-aspartate); poly(lactide-co- glycolide)-[(propylene oxide)-poly(ethylene oxide)]; poly(ethylene glycol) coated nanospheres; poly (isobutylcynoacrylate) nanocapsules; poly(γ-benzyl-L-glutamate)/poly(ethylene oxide; chitosan-poly(ethylene oxide) nanoparticles; methotrexate-o-carboxymethylate chitosan; as well as solid lipid nanoparticles (SLNs).

[0067] It is also contemplated thai the bioactive agent or agents could be formulated as microcapsules using materials such as multiporous beads of chitosan; coated alginate microspheres; N-(aminoalkyl) chitosan microspheres; chitosan/calcium alginate beads; poly(adipic anhydride) microspheres; gellan-gum beads; poly(D, L-lactide-co-glycolide) microspheres; alginate-poly-L-lysine microcapsules; crosslinked chitosan microspheres; chitosan/gelatin microspheres; crosslinked chitosan network beads with spacer groups; 1 ,5- diozepan-2-one (DXO) and D, L-dilactide (D,L-LA) microspheres.; triglyceride lipospheres; glulamate and TRH microspheres; polyelectrolyte complexes of sodium alginate chitosan; polypeptide microcapsules; Albumin microspheres.

[0068] It is also contemplated that the bioactive agents can be formulated as hydrogels and/or mucoadhesive agents as desired or required utilizing materials such as polyacrylates, chitosan, natural gums and/or cellulose derivatives.

[0069] It is also contemplated that the bioactive agent may be administered as plugs or pellets and can be formulated with permeation enhancers including but not limited to aprotinin; azone; benzalkonium chloride; cetylpyridinium chloride; cethylammonium bromide; cyclodextrin; dextran sulfate; lauric acid; propylene glycol; lysophosphatidylcholine; menthol; methoxysalicylate; methyloleate; oleic acid; phosphatidylcholine; polyoxyethylene; polysorbate 80; sodium EDTA; sodium glycocholate; sodium glycodeoxycholate; sodium lauryl sulfate; sodium salicylate; sodium taurocholate; sodium taurodeoxycholate; sulfoxides and vrious alkyl glycosides; xanthum gum; locust bean gum; chitosan; HPC; CMC; pectin; xantham gum; saponin; hyaluronic acid; benzyl esters; polycarbophil.

[0070] In order to better understand the invention set forth hering reference is made to the following non-limiting examples.

EXAMPLE 1

[0071] 1) Animals. Three rabbits (New Zealand ¾ lop) approximately 1.2 kg were used.

[0072] 2) SOD. Bovine Superoxide dismutase (sigma S2515) prepared at 10mg/ml in a viscous carrier vehicle (carboxymethylcellulose solution, 5%, average M_w ~700,000) containing 0.25% methylene blue as a visual marker,

[0073] 3) Injection technique. Rabbits were anesthetized by the injection of Ketamine

(50mg/kg) and Xylazine (5mg/kg). Instruments were applied to maintain the eye of the rabbit open, and facilitate the location of the lacrimal punctum. After visual confirmation of the punctum opening, a sterilized Hamilton syringe with a blunt needle was slowly inserted into the punctum to a depth of approximately 1 millimeter. When suitably inserted, 100 μl of SOD/CMC solution was injected slowly. The needle was then slowly retracted to avoid displacement of the solution. The rabbits were allowed to recover from the anesthetic and were returned to normal housing. The eyes were inspected daily for any unexpected problems, such as infection or inflammation, and any leakage of the preparation.

[0074] 4) Blood Samples. The rabbits were bled by ear puncture to obtained ImI of blood prior to the experiment, and at 24 hours, 48 hours, 72 hours, 7 days, 14 days and 21 days post punctum loading. Sera were separated and stored at -80c for ELISA assays. [0075] 5) Assay for SOD enzymatic activity. SOD Assay kit- WST (Fluka 19160) was used to determine SOD activity by utilizing Dojindo's highly water-soluble tetrazolium salt (WST-1), which produces a water-soluble formazan dye upon reduction with a superoxide anion. The rate of the reduction with O₂ is linear relative to the xanthine oxidase activity, and is inhibited by SOD. Therefore, the IC50 (50% inhibition activity of SOD or SOD-like material) can be determined by a colorimetric method. The assay was conducted in accordance with the manufacturers instructions. Using a 96 well plate, 20ul of rabbit sera (diluted 1 :100) was added to 200ul of WST working solution and mixed. Then 20ul of enzyme working solution was added. After incubation at 37°C for 20 minutes, the plate was read for absorbance at 450nm using a microplate reader, and enzyme activity expressed as optical density units corrected for background.

[0076] 6) ELISA for SOD levels. ELISA assays were developed to determine the plasma levels of SOD. 50ul of rabbit sera (1 : 1000 diluted in PBS) or a standard SOD solution was added to each well, and incubated at 4°C overnight. After washing 6 times with PBS/Tween, the plate was blocked by the addition of 200ul of 5% milk solution in PBS, and incubated at room temperature for 6 hours. The level of SOD was detected by the addition of the anti-SOD antibody conjugated to biotin. (Nordic Immunology NEl 52/Bio). Following incubation at 4°C overnight and washing, 100ul of streptavidin conjugated to alkaline phosphatase was added, and incubation continued for 60 minutes at 37°C. After washing 6 times with PBS/Tween, paranitrophenyl phosphate solution was added, and the color development allowed proceeding for 5 to 10 minutes. Absorbance was determined at 405 nm using a microplate phosphate (Molecular Devices Model 340).

Results

[0077] Administration Technique. Injection of 100ul solution into the punctum was easily carried out with ease. The administration technique suggests that a slightly larger volume, up to

200ul could be injected without loss of the solution. No signs of distress or subsequent development of eye inflammation were encountered at any point in the study.

[0078] SOD Activity Assay. The SOD activity assay generated a standard curve with first order rate kinetics (Figure 1 below) consistent for a typical enzymatic reaction. The standard curve indicated sensitivity over a range of 0.06 units/ml to 15 units/ml, with quenching occurring at levels in excess of 15 units/ml.

[0079] Using regression analysis from the standard curve, and applying corrections for the background levels of SOD activity detected in pre-bleed sera, the levels of SOD activity in sera following punctum loading in the three rabbits are shown in Table 1 below.

[0080] SOD levels by ELISA. ELISA development revealed that the Nordic antiserum anti-SOD antibody produced a linear standard curve over the dose range tested (Figure 2 below).

[0081] The plot of the ELISA results for the rabbit sera over the experimental course is shown in Figure 3 below. The data show a consistent increase in bovine SOD levels in sera in all three rabbits, reaching a peak at two days post punctum loading. However, a rapid decay in SOD levels occurred immediately after this peak, and SOD levels returned to background levels by three days post injection.

[0082] This study demonstrates the feasibility of loading SOD enzyme into the punctum without degradation. Positive levels of the SOD protein were detected in the rabbit blood following punctum loading, which was confirmed using two assay methods. The assay results showed that the protein was absorbed efficiently and the level detected in the serum reached potentially therapeutic levels.

Claims

CLAIMSWhat is claimed is:

1. A method for delivering at least one bioactive material into the bloodstream of a patient, the method comprising introducing at least a portion of the bioactive material to the bloodstream through a nasolacrimal drainage system of the patient.

2. The method of claim 1 wherein the bioactive material comprises at least one of a peptide or protein.

3. The method of claim 2 wherein the peptide or protein is at least one of biologicals, recombinant therapeutics, and synthetics.

4. The method of claim 1, 2 or 3 wherein the at least a portion of the bioactive material is introduced to the nasolacrimal drainage system by exfiltration through at least one punctum.

5. The method of claim 1, 2, 3 or 4 wherein the bioactive material is a recombinant therapeutic comprising at least one of superoxide dismutase (SOD), streptokinase (Streptase®), asparaginase, rhDNAse (Pulmozyme®), tissue plasminogen activator (Activase), imiglucerase (Cerezyme®), epoetin alfa (Procrit), epoetin alfa (Epogen), filgrastim (Neupogen), pegfilgrastim (Neulasta), insulin systemic (Novolin), interferon beta-1a (Avonex), pegylated interferon alpha (PEG-Intron A franchise), etanercept (Enbrel), darbepoetin alfa (Aranesp), epoetin-beta (NeoRecormon), and somatotropin.

6. The method of claim 1, 2, 3, 4 or 5 wherein the bioactive material is absorbed by at least one of a canaliculus, a lacrimal sac, an inferior meatus, a concha, an ampulia and a choroid.

7. The method of claim 1, 2, 3, 4, 5, or 6 wherein the bioactive material possesses efficacy against at least one of infectious disease, cardiovasculars, diabetes, cancer, inflammatory disease, neurological disorders, and immunological disorders.

8. The method of claim 1, 2, 3, 4, 5 or 6 wherein the bioactive material is in the form of at least one of solids, liquids, semisolids, lyophils, or extracts; and wherein the solids are in the form of tablets, granules, troches, lozenges, coated dosage forms, hard and soft gelatin capsules, ointments, pastes, creams, lotions, and liniments and the liquids are in the form of solutions, suspensions or emulsions.

9. The method of claim 4 wherein the bioactive material introduced to the punctum is in a pharmaceutical formulation including at least one of rapid-release, delayed-release and time controlled-release formulations.

10. The method of any of the preceding claims wherein the bioactive material comprises at least one of Poly(urethanes), Poly(siloxanes) or silicones, Poly(methyl methacrylate), Poly(vinyl alcohol), Poly(ethylene), Poly(vinyl pyrrolidone), Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone), Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly( ethylene glycol), Poly(methacrylic acid), Polylactides (PLA), Polyglycolides (PGA), Poly(lactide-co-glycolides) (PLGA), Polyanhydrides, Polyorthoesters, sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC).1

11. The method of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as nanoparticles using at least one of Poly(ethylene oxide)-poly(L-lactic acid)/poly(beta-benzyl-L-aspartate), Poly(lactide-co-glycolide)-[(propylene oxide)-poly( ethylene oxide)], Poly(ethylene glycol) coated nanospheres, Poly (isobutylcynoacrylate) nanocapsules, Poly(γ-benzyl-L-glutamate)/poly(ethylene oxide, Chitosan- poly(ethylene oxide) nanoparticles, Methotrexate-o-carboxymethylate chitosan, and Solid lipid nanoparticles (SLNs).

12. The method of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as microcapsules using Multiporous beads of chitosan, Coated alginate microspheres, N-(aminoalkyl) chitosan microspheres, Chitosan/calcium alginate beads, Poly(adipic anhydride) microspheres, Gellan-gum beads, PoIy(D, L-lactide-co- glycolide) microspheres, Alginate-poly-L-lysine microcapsules, Crosslinked chitosan microspheres, Chitosan/gelatin microspheres, Crosslinked chitosan network beads with spacer groups, l,5-diozepan-2-one (DXO) and D, L-dilactide (D,L-LA) microspheres, Triglyceride lipospheres, Glutamate and TRH microspheres, Polyelectrolyte complexes of sodium alginate chitosan, Polypeptide microcapsules and Albumin microspheres.

13. The method of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as hydrogels or mucoadhesives using Polyacrylates and chitosan or natural gums and cellulose derivatives.

14. The method of any of the preceding claims wherein the bioactive material is formulated as at least one of a plug or pellet.

15. The method of any of the preceding claims wherein the bioactive material further comprises a permeation enhancer.

16. The method of claim 15 wherein the permeation enhancer comprises at least one of Aprotinin, Azone, Benzalkonium chloride, Cetylpyridinium chloride, Cethylammonium bromide, Cyclodextrin, Dextran sulfate, Laurie acid, Propylene glycol, Lysophosphatidylcholine, Menthol, Methoxysalicylate, Methyloleate, Oleic acid, Phosphatidylcholine, Polyoxyethylene, Polysorbate 80, Sodium EDTA, Sodium glycocholate, Sodium glycodeoxycholate, Sodium lauryl sulfate, Sodium salicylate, Sodium taurocholate, Sodium taurodeoxycholate, Sulfoxides and various alkyl glycosides, Xanthum gum, Locust bean gum, Chitosan, HPC, CMC, Pectin, Xantham gum, saponin, Hyaluronic acid, Benzyl esters, Polycarbophil.

17. A method for delivering at least one therapeutic agent into the bloodstream of a patient, the method comprising: introducing at least a portion of the therapeutic agent to a nasolacrimal drainage system of the patient by delivering the therapeutic agent to at least one punctum of the patient; exfiltrating the therapeutic agent through the at least one punctum to the nasolacrimal drainage system; absorbing the therapeutic agent through at least one of a canaliculum, inferior meatus, ampulum, lacrimal sac, concha and choroid, wherein the therapeutic agent comprises at least one of a peptide or protein.

18. The method of claim 17 wherein the therapeutic agent further comprises at least one of a controlled release formulation and a permeation enhancer.

19. The method of claim 17 or 18 wherein the therapeutic agent is formulated into at least one of a solid, liquid, nanoparticle, microcapsule, hydrogen or mucoadhesive.

20. A kit for delivering bioactive materials through a punctum, the kit comprising a device having an exit orifice configured to contact or enter a punctum , at least one reservoir for containing a bioactive material, wherein the bioactive material contained in the reservoir is a peptide or protein, and means for delivering the bioactive material through the punctum through the exit orifice.

21. The kit of claim 20 wherein the bioactive material contained in the reservoir is a recombinant therapeutic comprising at least one of superoxide dismutase (SOD), streptokinase (Streptase®), asparaginase, rhDNAse (Pulmozyme®), tissue plasminogen activator (Activase), imiglucerase (Cerezyme®), epoetin alfa (Procrit), epoetin alfa (Epogen), filgrastim (Neupogen), pegfilgrastim (Neulasta), insulin systemic (Novolin), interferon beta-1a (Avonex), pegylated interferon alpha (PEG-Intron A franchise), etanercept (Enbrel), darbepoetin alfa (Aranesp), epoetin-beta (NeoRecormon), and somatotropin.

22. The kit of claim 20 or 21 wherein the exit orifice is configured to deliver the bioactive material for absorption by at least one of a canaliculus, a lacrimal sac, an inferior meatus, a concha, an ampulia and a choroid.

23. The kit of claim 20, 21 or 22 wherein the bioactive material contained in the reservoir is in the form of at least one of solids, liquids, semisolids, lyophils, or extracts; and wherein the solids are in the form of tablets, granules, troches, lozenges, coated dosage forms, hard and soft gelatin capsules, ointments, pastes, creams, lotions, and liniments and the liquids are in the form of solutions, suspensions or emulsions.

24. The kit of claim 20, 21, 22 or 23 wherein the bioactive material contained in the reservoir comprises at least one of Poly(urethanes), Poly(siloxanes) or silicones, Poly(methyl methacrylate), Polyvinyl alcohol), Poly(ethylene), Poly(vinyl pyrrolidone), Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone), Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(methacrylic acid), Polylactides (PLA), Polyglycolides (PGA), Poly(lactide-co-glycolides) (PLGA), Polyanhydrides, Polyorthoesters, sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC).

25. The kit of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as nanoparticles using at least one of Poly(ethylene oxide)-poly(L-lactic acid)/poly(beta-benzyl-L-aspartate), Poly(lactide-co-glycolide)-[(propylene oxide)-poly(ethylene oxide)], Poly(ethylene glycol) coated nanospheres, Poly (isobutylcynoacrylate) nanocapsules, Poly(γ-benzyl-L-glutamate)/poly(ethylene oxide, Chitosan- poly(ethylene oxide) nanoparticles, Methotrexate-o-carboxymethylate chitosan, and Solid lipid nanoparticles (SLNs).

26. The kit of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as microcapsules using Multiporous beads of chitosan, Coated alginate microspheres, N-(aminoalkyl) chitosan microspheres, Chitosan/calcium alginate beads, Poly(adipic anhydride) microspheres, Gellan-gum beads, PoIy(D, L-lactide-co- glycolide) microspheres, Alginate-poly-L-lysine microcapsules, Crosslinked chitosan microspheres, Chitosan/gelatin microspheres, Crosslinked chitosan network beads with spacer groups, 1,5-diozepan-2-one (DXO) and D, L-dilactide (D,L-LA) microspheres, Triglyceride lipospheres, Glutamate and TRH microspheres, Polyelectrolyte complexes of sodium alginate chitosan, Polypeptide microcapsules and Albumin microspheres.

27. The kit of any of the preceding claims wherein the bioactive material is a pharmaceutical formulation and is formulated as hydrogels or mucoadhesives using Polyacrylates and chitosan or natural gums and cellulose derivatives.

28. The kit of any of the preceding claims wherein the bioactive material further comprises a permeation enhancer.