Patent No. 7033598 Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal

 

Patent No. 7033598

Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal (Lerner, Apr 25, 2006) 

Abstract:

Disclosed are invasive and non-invasive central nervous system (CNS) drug delivery methods and devices for use in these methods that essentially circumvent the blood-brain barrier. More specifically, the disclosed methods and devices utilize iontophoresis as delivery technique that allows for enhanced delivery of a biologically active agent into the CNS of a mammal as well as for (pre)-programmable and controlled transport.

 

Notes:

FIELD OF THE INVENTION

The present invention relates to delivery methods and devices for effectively introducing a biologically active agent into deeper layers of the mammalian central nervous system (CNS). More specifically the invention relates to both invasive and non-invasive methods and devices for enhanced and controlled delivery of said agents into the mammalian CNS while circumventing the blood-brain barrier (BBB).

BACKGROUND OF THE INVENTION

A variety of approaches currently exist for delivering biologically active agents to the CNS. These include, among possible others, oral administration, intravenous--, intramuscular--and transcutaneous administration. All of the above drug delivery approaches tend to be systemic. Meaning that the drug is delivered into the systemic circulation, being carried to all internal organs and tissues and it has to pass through the blood-brain barrier (BBB) in order to access the CNS. Obviously, all other organs are being exposed to the drug, which may lead to a high incidence of side effects, particularly with those medications toxic to certain organs (e.g. nephrotoxic, hepatotoxic etc.). Most importantly, the therapeutic efficacy of numerous highly effective biologically active agents (e.g. large compounds, hydrophilic and charged substances such as peptides) is restricted, because they cannot or poorly penetrate the BBB, resulting in sub-therapeutic brain levels of these substances. High systemic levels have to be generated, in order to create therapeutic concentrations in the CNS, but for many therapeutic substances even this strategy is not always effective. Therefore, there is a large interest in development of alternative drug delivery methods for the central nervous system. 

The above strategies are based on a pharmacological approach to solve the problem of BBB transport. Another strategy often employed in brain delivery is the use of invasive methods such as intraventricular infusion systems, intracerebral (polymeric) implants, transplantation of genetically engineered protein-secreting cells and cell implants. These methods are unfortunately only effective for drug delivery to the surface of the brain or to cells immediately adjacent to the depot or infusion site and can be used for example in the treatment of carcinomatous infiltration of the meninges. However, these methods have many limitations because effective drug concentrations in brain parenchyma cannot be achieved. There are two reasons for the poor drug distribution in the brain following local delivery from a depot or infusion site. At first the efficacy of diffusion decreases with the square of the distance and at second, molecules that are highly diffusible will be immediately transported out of the brain by means of transport across local capillaries.

Diffusion in the brain is slow and it has been reported that the time required to obtain 50% equilibration over distances of approximately 1 cm may take hours to days. Administration directly into the cerebrospinal fluid (CSF) will result in significant drug levels in only the outer few millimeters of the tissue adjacent to the ventricular and subarachnoid spaces. Another disadvantage of intraventricular infusion is the occurrence of drug distribution only to the ipsilateral brain, because of the unidirectional flow of CSF within the brain. Intraventricular administration can be compared with a slow, intravenous infusion causing the drug to be rapidly eliminated out of the brain, because the CSF volume in humans is completely recycled every four to five hours, the drug is thus readily distributed into the peripheral blood stream.

Drug distribution from the matrix of a polymeric implant or catheter of a CNS delivery device is based on passive diffusion, which is a slow process. During diffusion the drug may be subjected to substantial metabolism and clearance. As a result, the volume of tissue exposed to the drug is very small. The treatment volume of a polymeric implant or intraventricular infusion has been determined to be less than 1 mm and this is true for both small and large substances. The limited migration distance has been demonstrated with small molecules and with large molecules such as nerve growth factor (NGF). A consequence of the limited diffusion distance is that cells immediately adjacent to the intracerebral implant are being exposed to high and often toxic concentrations of the drug.

The maximal penetration of drug into brain parenchyma is <1 mm regardless of the mode of administration (intracerebral implant, microdialysis within the brain or intracerebroventricular infusion). This imposes a severe limitation in clinical situations where much larger treatment regions may be required.

Delivery through a chronically implanted canula in the CNS is described by Hargraves et al. and Yebenes et al. Harbaugh et al. described the use of implantable infusion pumps.

U.S. Pat. No. 5,720,720 discloses a convection-enhanced delivery catheter and method adapted to increase the migration distance of the infused drug by maintaining a pressure gradient during interstitial infusion. Two to ten-fold larger treatment volumes may be achieved following high-flow infusion for 12 hours using a microinfusion rate of 3 mu.l/min than can be achieved with low-flow infusion delivering the same mass using an infusion rate of 0.05 mu.l/min. Despite its large improvement in delivery efficiency this method has also some disadvantages such as the long infusion time, the risk of leakage of drug and the limited control of the distribution pattern within anisotropic media such as the white matter.

As with all catheter devices for intracerebral drug delivery, insertion of a device into a ventricle requires a risky surgical intervention that may cause serious tissue damage.

The present invention overcomes the disadvantages such as limited penetration depth of existing implantable delivery methods by using iontophoresis as a drug delivery enhancement technique. Iontophoresis has been defined as the active introduction of ionised molecules into tissues by means of an electric current. The technique has been used to enhance drug delivery into tissues underlying the donor electrode (e.g. skin) as well as to the general blood circulation, thus providing systemic delivery of a drug to the entire body. Iontophoresis devices require at least two electrodes, both being in electrical contact with some portion of a biological membrane surface of the body. One electrode commonly referred to as the "donor" or "active" electrode, is the electrode from which the biologically active substance, such as a drug or prodrug, is delivered into the body. Another electrode having an opposite polarity functions to complete the electric circuit between the body and the electrical power source. This electrode is commonly referred to as the "receptor" or "passive" electrode. During iontophoresis, an electrical potential is applied over the electrodes, in order to create an electrical current to pass through the drug solution and the adjacent tissue.

Iontophoretic drug administration into body cavities by means of a catheter type of electrode has been first disclosed about 95 years ago. The Russians were in this field very productive and during the 1970's and 1980's a considerable number of patents were issued (e.g. SU Nos 532,890; 843,999; 1,005796). Recently, patents have been issued that disclose the treatment of blood-vessel related disorders (e.g. restenosis), bladder, uterus, urethra and prostate disorders. U.S. Pat. Nos. 6,219,557; 5,588,961; 5,843016; 5,486,160; 5,222,936; 5,232,441; 5,401,239 and 5,728,068 disclose different types of iontophoresis catheters for insertion into hollow, tubular organs (bladder, urethra and prostate) or into blood vessels. An implantable system for myocardial iontophoretic delivery of drugs to the heart is disclosed in U.S. Pat. No. 5,087,243.

Reference may be made to U.S. Pat. No. 5,807,306, which describes an iontophoresis catheter device for delivering a drug contained in a polymer matrix into internal tissue. The disclosed catheter may thus be an ideal tool for selective and controlled delivery to any body passageway or hollow organ. Because the drug is contained in a polymeric matrix, the risk of leakage typically associated with catheter devices is practically negligible. However, the disclosed device is not adapted to be implanted in the brain and is not suitable for long-term treatment. Furthermore, the device requires manual operation and it requires serious surgical intervention for intracerebral installation of the catheter.

The parent U.S. patent application of this CIP, Ser. No. 09/197,133 relates to a non-invasive method and device for delivery of a biologically active agent that is transported by means of iontophoresis and/or phonophoresis directly to the CNS using the olfactory pathway to the brain and thereby circumventing the BBB. This method we have called transnasal iontophoretic delivery. The present invention describes besides the non-invasive also invasive methods and devices for enhanced and controlled delivery of a biologically active agent to the CNS that also circumvents the BBB.

In humans and primates, the olfactory epithelium or olfactory mucosa is located at the top of the nasal cavity between the central nasal septum and the lateral wall of each main nasal passage. This region of the nasal cavity, which is free of airflow, lies just under the cribriform plate of the ethmoid bone that separates the nasal and cranial cavities. In humans the olfactory epithelium covers an area in the nose of approximately 2 cm.sup.2 to 10 cm.sup.2. The total olfactory surface area varies with age and between individuals. The olfactory area can be reached through the naris following the nasal septum in a superior and posterior direction. The middle turbinate, which closely opposes the septum usually prevents access to this region, fortunately, this obstruction is not surmountable.

In the last decade a number of articles were published that describe the delivery of drugs into the brain by administering the drug in the olfactory area and also a small number of patents have been issued that describe the use of the olfactory pathways to the brain as possible alternative drug delivery methods. For example, U.S. Pat. No. 5,624,898 issued by Frey W. H.; WO 033813A1 issued by Frey W. H.; WO 09901229A1 issued by Gizurarson S. and WO 044350A1 issued by Cevc et al. These patents all relate to the passive delivery of substances to the brain using the olfactory pathways. The agent is administered in the olfactory region and transport of the agent is based on passive diffusion through the olfactory epithelium. However, compounds that are hydrophilic, charged and/or larger than 300 Dalton may be not delivered in therapeutic effective amounts by the methods described in the cited references. These compounds, but also all other compounds may be delivered more rapidly and more effectively by means of a physical enhancement technique such as electrotransport and/or phonophoresis (sonophoresis). The use of an enhancement technique such as electrotransport has the additional advantage that it can provide a dose- and rate-controlled delivery of the biologically active agent and the dose can be pre-programmed according to individual needs.

Literature provides examples of methods to treat the nasal (respiratory) mucosa by means of iontophoresis, electrophoresis, and phonophoresis for allergy, rhinitis, sinusitis etc., and there are also papers that describe the use of nasal iontophoresis for systemic drug delivery. Already in 1937 Bailey L. et al. described the use of intranasal zinc iontophoresis to treat hay fever. (Bailey L. D. and Shields C.; Br. Med J. 1, 808, 1937). Other examples of nasal iontophoresis can be found in literature as for instance in; Weir et al., J. Laryngol. Otol. 81 (10): 1143-1150 (1967), Dadiomova et al., Vestn. Dermatol. Venerol. 43(7):72-74 (1969), Dainiak et al., Vestn. Otorinolaringol. May-June; (3): 26-34 (1979); Sokolova et al., Vestn. Otorinolaringol. November-December; (6):57-60 (1979); Krotkova et al., Zh. Vopr. Neirokhir. Im. N. N. Burdenko May-June; (3): 44-47 (1980); Buzek et al., Cas. Lek. Cesk.; 120 (51): 1561-1565 (1981) and Gronfors et al., Med. Prog. Technol.; 17 (2): 119-128 (1991). Examples of nasal iontophoresis electrodes for systemic delivery or local delivery are described in the following patents: U.S. Pat. No. 5,298,017 issued by Theeuwes et al., SU-992075 issued by Kens et al. and U.S. Pat. No. 6,001,088 issued by Roberts et al. that describes a method for delivery of a biologically active agent to the eye following iontophoresis through the nasal epithelium.

Systemic nasal drug delivery implicates that drugs are delivered through the respiratory epithelium of the nasal cavity. In contrast to the olfactory mucosa, the respiratory epithelium is easy accessible by means of for example; nose drops, nasal sprays and a possible iontophoresis or phonophoresis probe. However, the major reason why respiratory epithelium is the target site of nasal drug administration is its rich underlying vascular network, especially in the Kiesselbach's area. These blood vessels can be accessed immediately following absorption and blood flow distributes the drug throughout the rest of the body. The present invention is based on enhanced delivery of a biologically active agent through the olfactory epithelium of the nasal cavity. Vascularization in the olfactory region is much less compared to the anterior part of the nasal cavity. The olfactory epithelium has distinct anatomic differences with the respiratory epithelium (Graziadei P. P. C. and Monti-Graziadei, 1985, Ann.NYacad.Sci, 457,127-145). The olfactory epithelium being a sensitive neuroepithelium with poor regeneration properties whereas the respiratory epithelium is an "ordinary" squamous mucosal epithelium with good regeneration properties and having mucocilliary clearance. Due to the differences between these two types of epithelium and especially to the delicate nature of olfactory neuroepithelium compared to the respiratory mucosa, nasal compositions for the respiratory nasal mucosa will not automatically be appropriate for the olfactory mucosa. Also, iontophoresis parameters (e.g. current strength, wave-form, frequency, duration) for enhanced olfactory drug delivery will differ from enhanced transport through respiratory nasal mucosa use of nasal iontophoresis according to the present invention requires specific physicotechnical properties of the nasal electrode(s) that differ from the nasal electrodes described for local and systemic delivery through the respiratory epithelium. For example, the electrode must have such a shape to allow it to be inserted into the olfactory region through the olfactory cleft and to make an intimate contact with the olfactory mucosa.

An alternate BBB circumventing pathway to the brain is provided by the optic nerve. The optic nerve, which is about 4 cm long, is directed backwards and medially through the posterior part of the orbital cavity. It then runs through the optic canal into cranial cavity and joins the optic chiasma. The optic nerve is enclosed in three sheaths, which are continuous with the membranes of the brain, and are prolonged as far as the back of the eyeball. Therefore, there is a direct connection between the optic nerve and the brain structures. Itaya and van Hoessen described transneuronal retrograde labeling of neurons in the stratum griseum superficiale of the superior colliculus following intra-ocular injection of wheat germ agglutinin-horseradish peroxidase. A study of the distribution of wheat germ agglutinin-horseradish peroxidase in the visual system following intra-ocular injections in the chick, rat and monkey confirmed early findings of transneural transport of this conjugate in vivo. It is therefore envisioned that a biologically active agent can be delivered direct to the CNS by a non-invasive delivery method and apparatus that utilises the ocular pathway that circumvents the BBB.

SUMMARY OF THE INVENTION

The present invention provides invasive and non-invasive methods and devices for enhanced and controlled delivery of a biologically active agent directly into the CNS, thereby circumventing essentially the blood-brain barrier. The invasive methods involve a surgical intervention that is limited to a minimum compared to existing methods, because the delivery system is installed at an extracerebral location i.e. for example in the cranium, the epidural, or subdural spaces, on the brain surface or intrabrain. The non-invasive methods and devices utilise the olfactory or ocular pathway to the CNS and thus circumvent the BBB. Both invasive and non-invasive methods allow for achievement of therapeutic brain levels of a biologically active agent while effectively reducing the application or infusion time of said agent compared to existing methods.

In view of the limitations of existing CNS delivery systems, it is an object of the present invention to provide a method and device for enhanced and controlled administration of a biologically active agent that allows for effective concentrations of said agent in deeper tissue layers of the CNS while essentially circumventing the systemic compartment and the blood-brain barrier.

It is an object of the present invention to provide a method and device for enhanced and controlled CNS administration of a biologically active agent that requires a minimum of surgical intervention and that allows for a high level of safety with a minimum of local side effects.

It is a further object of the invention to provide a device of such design and made of such materials, as well as such a method for administration of a biologically active agent into the CNS that promotes high patient compliance and acceptance.

It is yet another object of the invention to provide a method and device for controlled and enhanced delivery of a biologically active agent into the CNS that is regulated by a feedback signal.

It is a further object of the present invention to thus treat CNS disorders.

These and other objects are accomplished by providing drug delivery methods and devices that use iontophoresis for controlled and enhanced delivery of a biologically active agent into the CNS. Phonophoresis may be chosen as an alternate delivery technique for the non-invasive delivery methods and devices of the present invention.

For the purpose of this invention, "iontophoresis" is defined as any form of electrotransport of a substance through mammalian tissue induced or enhanced by the application of an electrical potential. Thus, the term "iontophoresis" as used herein includes without limitation previously defined terms such as iontophoresis, electrotransport, iontokinesis and electroosmosis, and the combination of thereof, which comprises the transport of a substance induced or enhanced by the application of an electric potential.

"Olfactory region" or "olfactory area" of the human nose for the purpose of the disclosed invention defines the area of nasal mucosa that covers the olfactory cleft, as well as the septal mucosa of the superior and middle turbinates in the posterior and middle thirds of the nose.

As used in conjunction with the disclosed invention, the term "biologically active agent" as defined herein, is an agent, or its pharmaceutically acceptable salt, or mixture of compounds, which has therapeutic, prophylactic, pharmacological, physiological or diagnostic effects on a mammal and may also include one compound or mixture of compounds that produce more than one of these effects. Suitable therapeutic, pharmacological, physiological and/or prophylactic biologically active agents can be selected from the following listed, and are given as examples and without limitation: amino acids, anabolics, analgesics and antagonists, anaesthetics, anti-adrenergic agents, anti-asthmatics, anti-atherosclerotics, antibacterials, anticholesterolics, anti-coagulants, antidepressants, antidotes, anti-emetics, anti-epileptic drugs, anti-fibrinolytics, anti-inflammatory agents, antihypertensives, antimetabolites, antimigraine agents, antimycotics, antinauseants, antineoplastics, anti-obesity agents, anti-Parkinson agents, antiprotozoals, antipsychotics, antirheumatics, antiseptics, antivertigo agents, antivirals, appetite stimulants, bacterial vaccines, bioflavonoids, calcium channel blockers, capillary stabilizing agents, coagulants, corticosteroids, detoxifying agents for cytostatic treatment, diagnostic agents (like contrast media, radiopaque agents and radioisotopes), drugs for treatment of chronic alcoholism, electrolytes, enzymes, enzyme inhibitors, ferments, ferment inhibitors, gangliosides and ganglioside derivatives, hemostatics, hormones, hormone antagonists, hypnotics, immunomodulators, immunostimulants, immunosuppressants, minerals, muscle relaxants, neuromodulators, neurotransmitters and nootropics, osmotic diuretics, parasympatholytics, para-sympathomimetics, peptides, proteins, psychostimulants, respiratory stimulants, sedatives, serum lipid reducing agents, smooth muscle relaxants, sympatholytics, sympathomimetics, vasodilators, vasoprotectives, vectors for gene therapy, viral vaccines, viruses, vitamins, oligonucleotides and derivatives, and any therapeutic agent capable of affecting the nervous system.

Examples of biologically active agents, which may be preferentially administered using either the invasive or non-invasive methods disclosed here for enhanced delivery directly into the CNS and thereby essentially avoiding the systemic circulation include those biologically active agents degraded in the gastrointestinal tract, metabolised in an internal organ or in the blood, rapidly excreted from the bloodstream (e.g. through kidney clearance), and those with limited penetration of the blood-brain barrier. Also, those agents with systemic side effects will benefit from direct administration in the CNS avoiding the blood stream. Further those biologically active agents that at least partly target the CNS although the underlying disease may have systemic clinical manifestations (e.g. alpha-2-agonists and hypertension). Also, those that target the neural components of the olfactory pathway (e.g. therapeutics that promote regeneration of the olfactory bulb) or those that target neural components of the ocular pathway. Iontophoresis and/or phonophoresis provide thus a means for active transport of a biologically active agent into and/or through the ocular pathway or into and/or through the nasal mucosa, and into the olfactory pathways, and/or into the CNS. Also, iontophoresis and/or phonophoresis provide an active transport means to rapidly and effectively transport a biologically active agent out of the delivery device to the olfactory area of nasal mucosa to be treated or into the underlying tissues.