WO2001043528A2 - Devices and methods in intracerebrospinal delivery of morphine-6-glucuronide - Google Patents

Description

DEVICES AND METHODS IN INTRACEREBROSPINAL DELIVERY OF

MORPHINE-6-GLUCURONIDE

FIELD OF THE INVENTION The invention relates to drug delivery devices in the administration of drugs to the central nervous system

BACKGROUND OF THE INVENTION

Morphine is the opioid drug of choice for management of chronic pain This preference for morphine is due at least m part to its low cost, the ability of the drug to provide relief from pam of a vanety of origins, and the vast experience with this drug Despite the apparent advantages of morphine, many experts in pain management believe that morphine and other narcotics are under- prescribed for chronic pain patients

One major reason for hesitancy in prescription of opioids such as morphine is the risk of the side effects associated with long-term administration Examples of such side effects include, but are not necessarily limited to, severe reduced cough reflex, bronchial spasms, release of hista ine, stimulated release of adrenalin, nausea, vomiting, peripheral vasodilation, orthostatic hypotension, vagal impact on the heart, contraction of smooth muscles (sphincters), reduced peristaltic motility in the gastrointestinal tract and associated constipation, urinary retention, changes in the regulation of body temperature and sleep pattern, as well as the development of opioid tolerance and addiction Patients who develop opioid tolerance require increased doses to achieve a satisfactory analgesic effect, and risk the development of further undesirable side effects such as respiratory depression, which can be life threatening Discontinuing opioid administration m a dependent subject results in the onset of withdrawal symptoms, which itself can be severely painful

Where the concerns regarding side effects might be outweighed by the seπous need for pain relief as in terminally ill patients, many doctors still avoid prescribing narcotics due to their concerns of the abuse of surplus medication by others in contact with the patient, or are even concerned that their frequent prescπption of the drug might lead to criminal investigation As a result, many chronic pain patients do not receive the best available therapy despite the fact that such is readily available

After systemic administration (e g , oral, subcutaneous, intravenous, etc ), morphine is metabolized About 90% of morphine is converted to its metabolites, principally by glucuronidation Approximately 45-55% of morphme is metabolized to morphιne-3-glucuromde (M3G) and another 10-15% is metabolized to morphme-6-glucuronιde (also known as morphine- 6β-glucuronιde or glucuronic acιd-6-(7,8-dιdehydro-4,5 epoxy-17-methylmoφhman-3,6 diolyl) ester, referred to herein as M6G) Other minor metabolites include morphιne-3,6-dιglucuronιde, morphιne-3 -ethereal sulphate, normorph ne, normoφhme-6-glucuromde, normoφhιne-3- glucuromde, and codeine (for a review see Chnstrup (1997) ACTA Anaesth Scand 41 116-122) Of these metabolites, M6G binds opioid receptors (predominately the μ receptor), exhibits analgesic properties, and appears in plasma in clinically relevant levels following systemic administration of moφhme However, the metabolism of moφhine, as well as the influence of moφhme metabolites upon the moφhme's pharmacodynamics, are still not clearly understood and have only been subjected to limited investigation, particularly m situations of chronic use (see, e g , Chnstrup, supra, Kalman et al (1997) Reg Anesth 22 131-6, and Samuelsson et al (1993) Paw 52 179-85)

In recent years, interest in delivery of M6G to control pain in human subjects has increased Systemic routes for delivery of M6G have included transdermal delivery (see, e g , U S Pat No 5,705, 186) and nasal delivery (see, e g , U S Pat No 5,629,011) Central administration (e g , intraspinal or mtracerebroventricular delivery) of a bolus of M6G to human subjects has also been descπbed, though to a lesser extent Grace et al ((1996) Anesth Analg 83 1055-9) described delivery of an mtrathecal bolus of M6G for control of post-operative pain following total hip replacement, although this group did not observe any improvement in side effects relative to mtrathecal moφhine Morley et al ((1992) Lancet 340 1045) descnbed that administration of an mtrathecal bolus of M6G to one patient resulted in full relief from pam associated with disseminated colomc carcinoma Hanna et al ((1990) Br J Anaesth 64 547-50) reported that delivery of a bolus of M6G through an mtrathecal catheter provided greater analgesic activity than delivery of moφhme by the same route and with an equivalent incidence of side effects However, the conclusions of Hanna et al were later cnticized (Hardy (1991) Br J Anaesth 66 271 -4) Not all reports of pam relief following central administration of M6G have been positive For example, in one study administration of a bolus of mtrathecal M6G followed by bupivacame caused profound, delayed respiratory depression in opioid-naive sublets (Coe et al (1992) Br J Anaesth 69 221P)

As is evident from the above, while M6G has the potential to be a drug of choice for management of chronic pam, no conventional protocol for safe, effective administration that is associated with an acceptable range of side effects is available The present invention addresses this problem

SUMMARY OF THE INVENTION The invention features a method for management of chronic pam by mtracerebrospinal delivery of moφhιne-6-glucuronιde (M6G) or a bioactive derivative thereof In various embodiments, the invention involves delivery of M6G or a denvative thereof in a patterned fashion (e g , substantially continuous delivery) and/or at a relatively low volume rate, Drug delivery can be accomplished using an external or implanted pump, preferably an implanted pump A primary object of the invention is provide a method for convenient, long-term mtracerebrospinal delivery of M6G

Another object of the invention is to effectively treat conditions associated with pam by administration of M6G at a relatively low volumetric rate, so as to provide the drug in a therapeutically effective amount (e g , m an amount adequate to provide the subject relief from pain symptoms associated with the condition)

Delivery of a relatively low volume rate and/or dose of M6G, particularly a substantially constant, low volume rate and/or low mass dose, can provide for an improvement in adverse side effects that can be normally associated with delivery of opioid analgesics Given the adverse effects of opiate analgesics, this advantage is of considerable benefit to those requiring pain relief, particularly in relatively long term (e g , 1-4 weeks and longer) or chronic pam situations Furthermore, low volume delivery and/or low dose delivery is more cost-effective in that it requires a smaller volume of drug formulation and less drug for the selected treatment penod, which in turn increases the period of time between refilling of the drug reservoir The method of the invention can thus make effective pam management therapy available to a broader population The invention is also advantageous in that it facilitates delivery of M6G, a moφh ne denvative that, due to its potency, is less amenable to safe and effective delivery usmg conventional methods (e g , bolus mtraspmal injection) The present invention can be provided so as to accomplish consistent delivery of M6G at low dose and/or low volume rates (e g , on the order of nanoliters to milliliters per day) thereby eliminating the undesired overdosing and underdosmg inherently associated with bolus administration to provide safe, effective therapy while minimizing the risk of undesirable side effects

Where the method uses an lmplantable device, the invention has the additional advantage that it avoids the need for placement of external needles and/or external catheters m the subject, which provides sites subject to infection In addition, use of an implanted device mcreases patient compliance with a prescπbed therapeutic regimen, and substantially decreases or completely avoids the πsk of abuse or overdose of the drug

Another advantage of the invention is that delivery using an lmplantable drug delivery device affords greater mobility and easier outpatient management Furthermore, where M6G is delivered at low volume rates, the reservoir of the drug delivery device can be smaller and/or refilled or replaced less frequently These features further enhance the patient's comfort, convenience, and compliance and reduce the burden on the medical caretakers

Delivery of M6G according to the invention is advantageous over bolus delivery in several respects As noted above, in a bolus injection the entire drug formulation volume is delivered at once, and thus is usually associated with overdosing and underdosmg of drug Bolus administration is associated with overdosing because a larger than therapeutically effective amount of drug must be administered if the drug is to last until the next bolus dose Bolus administration is also associated with underdosing because the amount of drug present m the subject may be less than the therapeutically effective amount just prior to administration of the next bolus In addition, where drug delivery by bolus administration requires delivery of a relatively large volume of formulation, bolus administration can result m local tissue damage, and/or changes m the composition of the body fluid or tissue into which the drug is delivered (e g , changes in CSF composition) Delivery accordmg to the invention avoids these problems in that, for example, the required volume of drug formulation can be delivered over a longer peπod of time The delivery method of the invention thus minimizes disturbance of tissue at the delivery site (e g , the dura, epidural space, mtrathecal (t e , subarachnoid) space, etc ), which m turn minimizes or avoids adverse tissue reactions (e g , edema) In addition, delivery according to the invention yields more reproducible drug absoφtion and distribution mto the body without inflicting local tissue damage, and provides optimal drug dosing Furthermore, because the catheter used to facilitate low volume rate drug delivery is generally of relatively small dimensions (e g , on the order of 0 1 mm to about 6 mm outer diameter or, in some embodiments, even smaller), the degree of invasion and disturbance of tissues m order to access the lntracerebrospinal delivery site is minimized (e g , the size of puncture m the dura to access the subarachnoid space for mtrathecal delivery is relatively small)

The invention is also advantageous m that delivery directly to an mtracerebrospinal site allows for delivery of concentrated drug doses to the site at which therapy is needed while reducing the risk of side effects normally associated with systemic delivery of therapeutically effective doses of M6G

The invention is also advantageous in that delivery according to the invention exploits the hydrophihcity of M6G, which facilitates retention of the drug in the cerebrospinal fluid The invention also takes advantage of M6G's analgesic potency after mtracerebroventπcular or mtrathecal admmistration relative to the parent molecule (e g , an analgesic potency anywhere from 45 to 800 times greater than that of moφhme)

The invention is also advantageous in that it involves delivery of a drug that is not metabolized following administration according to the invention, thus making delivery of an effective dose more predictable

These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the methodology and compositions as more fully set forth below

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 illustrates delivery of M6G using an implantable pump connected to a drug delivery catheter positioned for delivery of drug to an mtracerebrospinal site, exemplified here by a site in the mtrathecal space

Fig 2 is a schematic providing a cut-away view of a catheter distal end positioned within the spine for mtrathecal delivery of M6G

Fig 3 is a schematic of a partial cut-away view illustrating delivery to an mtracerebrospinal site, here exemplified by an lntracerebroventπcular site in the bram, according to the invention

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present methods, devices, and compositions for mtracerebrospinal delivery of M6G are descπbed, it is to be understood that this invention is not limited to the specific methodology, formulations, and conditions susceptible to therapy descπbed as such may, of course, vary It is also to be understood that the terminology used herein is for the puφose of describmg particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims

It must be noted that as used herem and m the appended claims, the singular forms "a", "and", and "the" mclude plural referents unless the context clearly dictates otherwise Thus, for example, reference to "a drug delivery device" includes a plurality of such devices and reference to "the method of delivery" includes reference to equivalent steps and methods known to those skilled m the art, and so forth

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described

All publications mentioned herein are incoφorated herein by reference for the puφose of descπbmg and disclosing the compositions and methodologies which are descπbed in the publications which might be used m connection with the presently described invention The publications discussed herein are provided solely for their disclosure pπor to the filing date of the present application Nothing herein is to be construed as an admission that the invention is not entitled to antedate such a disclosure by virtue of prior invention

Definitions

The term "moφhιne-6-glucuronιde" (referred to herein as M6G) is meant to refer to a compound of the formula

as well as pharmaceutically acceptable salts thereof suitable for mtracerebrospinal admmistration "M6G denvative" is meant to refer to a bioactive denvative of M6G produced by either natural and/or synthetic processes, as well as pharmaceutically acceptable salts thereof suitable for admmistration according to the invention

The term "subject" is meant any subject, generally a mammal (e g , human, canine, felme, equine, etc ), to which delivery of M6G for management or control of pam, particularly chronic pain, is desired The term "therapeutically effective amount" is meant an amount of a therapeutic agent, or a volumetric or mass rate of delivery of a therapeutic agent, effective to facilitate a desired therapeutic effect, e g , alleviation of pain The precise desired therapeutic effect (e g , the degree of pain relief, and source of the pam relieved, etc ) will vary accordmg to the condition to be treated (e g , the condition with which chronic pam is associated), the formulation to be administered, and a variety of other factors that are appreciated by those of ordmary skill m the art In general, the method of the invention involves the suppression or mitigation of pam in a subject suffering from pam that may be associated with any of a vaπety of identifiable or unidentifiable etiologies The term "implantation site" is used to refer to a site withm the body of a subject at which a drug delivery device is introduced and positioned

"Delivery site" as used herein is meant to refer to an area of the body to which drug is delivered A delivery site within the spine is of particular interest in the present application, e g , epidural, subdural, mtrathecal, and the like "Drug delivery device" as used herem is meant to encompass any device, suitable for delivering a formulation to an mtracerebrospinal site accordmg to the invention, particularly a device adapted for complete or partial implantation "Drug delivery device" encompasses devices that are partially, substantially completely, or completely implanted "Pump" is used herein to refer to convective delivery systems in general "Drug delivery device" thus encompasses any device with any mechanism of action suitable for use in the invention, includmg diffusive, erodible, or convective systems, e g , osmotic pumps, biodegradable implants, electrodif usion systems, electrochemical systems, electroosmosis systems, vapor pressure pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps, erosion-based systems, or electromechanical systems Convective drug delivery devices are of particular interst The term "controlled drug delivery device" is meant to encompass any device wherein the release (e g , rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not the environment of use

"Patterned" or "temporal" as used m the context of drug delivery is meant delivery of drug m a pattern, generally a substantially regular pattern, over a pre-selected period of time (e g , other than a penod associated with, for example a bolus injection) "Patterned" or

"temporal" drug delivery is meant to encompass delivery of drug at an mcreasmg, decreasmg, substantially constant, or pulsatile, rate or range of rates (e g , amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic

By "substantially continuous" as used in, for example, the context of "substantially continuous delivery", is meant to refer to delivery of a substance (e g , a drug) in a manner that is substantially uninterrupted for a pre-selected peπod of drug delivery (other than a peπod associated with, for example, a bolus injection) Furthermore, "substantially continuous" drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e g , amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery By "low volume rate" as used herein with reference to mtracerebrospinal delivery of M6G is generally meant a volume rate of from about 10 nl/day to about 2 ml/day, generally from about 40 nl/day to about 1 ml/day, usually about 0 2 μl/day to about 0 5 ml/day, typically from about 1 0 μl/day to about 10 μl/day The actual volume rate may vary according to the specific lntracerebrospinal site selected The term "pam management or treatment" is used here to generally descπbe regression, suppression, or mitigation of pain so as to make the subject more comfortable as determined by subjective cnteπa, objective cπteπa, or both In general, pam is assessed subjectively by patient report, with the health professional takmg into consideration the patient's age, cultural background, environment, and other psychological background factors known to alter a person's subjective reaction to pam

"Treatment" as in is used herein to encompass, but not necessarily be limited to, a decrease m seventy of symptoms (e g , to provide partial or complete relief of pain) as well as management of a condition (e g , suppression of a symptom and/or conection of a defect associated with a condition to make the condition more tolerable for the subject (e g , to decrease the seventy or incidence of severe episodes of pam to improve the subject's quality of life, etc )

The term "proximal end" (or "first end") is used herem in connection with components and/or elements of the devices used herein that are closer to a clinician or other individual who is using the catheter and/or devices accordmg to the invention m a medical treatment setting Conversely, the term "distal end" (or "second end") is used herem m connection with components and/or elements that are closer to the treatment site within the body of the subject bemg treated The invention will now be descπbed in more detail INTRACEREBROSPINAL DELIVERY OF M6G

The present invention is based on delivery of moφhme-6-glucuronιde (M6G) or a denvative thereof to an mtracerebrospinal site in a manner that accomplishes administration of a therapeutically effective amount of drug (e g , an amount of M6G effective to alleviate pam) while avoiding or mitigating side effects that can be associated with bolus administration of the drug, and minimizing trauma or damage to the CNS It should be noted that where reference is made to M6G in the disclosure herein, such reference is intended to encompass delivery of active denvatives of M6G unless specifically noted otherwise In one embodiment, M6G is delivered m a patterned fashion, (e g , by substantially continuous delivery or other pattern other than, for example, single bolus delivery) In another embodiment, M6G is delivered at a relatively low volume rate

In general, the methods of the invention involve delivery where M6G is not released from an implanted or external reservoir of drug as a single bolus dose, but rather is introduced into the mtracerebrospmal site over time, generally gradually over time The invention thus provides for delivery of M6G so that a desired therapeutic effect (e g , at least some degree of pain relief) is maintained m the subject for a selected period of time, while, for example, avoiding side effects that can be associated with bolus delivery of M6G In one embodiment, M6G is delivered so that a therapeutically effective concentration of M6G is maintained within the target tissue of the subject over the desired treatment penod, e g , without overdosmg or underdosmg The methods of the invention can thus be carried out to avoid drug concentration "peaks" that can be associated with overdosage, as well as drug concentration "valleys" that can be associated with underdosage The invention can thus be carried out so that drug is delivered in an amount just above the sub- therapeutic/therapeutic threshold to provide for partial or complete pain relief In one aspect, the invention involves maintaining the concentration of drug within a therapeutically effective range m the subject's cerebrospmal fluid at or in the area of the mtracerebrospmal administration site over a pre-selected penod, which penod can range from hours to days to weeks, months, or years depending on the duration of therapy

Delivery of M6G accordmg to the invention can be accomplished usmg a drug delivery device and an attached catheter The catheter compnses a proximal end for permanent or removable attachment to the drug delivery device, and an implantable distal end for implantation at the desired mtracerebrospmal delivery site Drug is delivered to the mtracerebrospmal site by implanting a distal end of the drug delivery catheter at the selected delivery site, and delivering M6G from a drug delivery device attached to the proximal end of the catheter, through a lumen defined by the catheter, and to the mtracerebrospinal site adjacent the catheter distal end In all embodiments, at least the distal end of the catheter is implanted In other embodiments, the catheter is substantially completely implanted and attached to an external or partially implanted drug delivery device Alternatively, the catheter and drug delivery device can be fully implanted "mtracerebrospinal delivery site" is meant to include any site that allows access to the cerebrospmal fluid and/or access to spinal nerve roots mtracerebrospmal delivery sites include, but are not necessaπly limited to, mtrathecal (e g , a delivery site within the subarachnoid space), epidural (e g , a delivery site within the extradural space) or lntracerebroventπcular, with mtrathecal being preferred For mtraspmal delivery, the drug delivery catheter can be positioned for delivery to the mtracerebrospmal delivery site by threading the catheter between vertebrae of the spme anywhere along the neuraxis from cervical to sacral vertebrae In some embodiments, it may be preferable to access mtracerebrospmal delivery sites for mtraspmal delivery by placement of the catheter between the vertebrae LI and L2, L2 and L3, L3 and L4, or L4 and L5

The drug delivery catheter can be anchored at the mtracerebrospmal delivery site so as to minimize or avoid movement of the distal end of the catheter either within the space definmg the delivery site and/or to minimize the nsk of dislodging the catheter from the delivery site

Referring now to the figures, Figs 1 and 2 illustrate one embodiment of the invention in which drug is delivered from an implanted drug delivery device 10 to an mtracerebrospmal site, exemplified here by an mtrathecal site In this example, the drug delivery device 10 is positioned on the patient's back 5, and can be either implanted beneath the patient's skm as illustrated, or retained at an external site A formulation compnsmg M6G is delivered from device 10, into the attached proximal end 21 of catheter 20, through a lumen of catheter 20, and out catheter distal end 22 adjacent a delivery site within the spine 15

Fig 2 illustrates placement of catheter 20 within the mtrathecal space of the spine Catheter 20 is inserted through the dura 50 so that the distal end of the catheter 20 is positioned withm the subarachnoid space 60

Fig 3 illustrates placement of catheter 20 within an lntracerebroventπcular site In this example, a distal end of catheter 20 of drug delivery device 10 is positioned for delivery of drug to a site withm the brain, here exemplified as ventricle 590 In general, drug release device 30 is completely or partially implanted at a convenient subcutaneous implantation site 500, exemplified in Fig 3 as a subcutaneous site along the back of the subject's neck or on the subject's back The body of catheter 20 is implanted under the skin 560 and extends beneath the skm 560 from the implanted drug release device 30 at implantation site 500 to an access site provided in the skull 570 through which the catheter 20 is inserted for positioning of the distal end within a ventricle 590

Methods for implanting or otherwise positioning a drug delivery device or for implanting a catheter for mtracerebrospinal delivery are well known in the art In general, placement of the drug delivery device will be accomplished usmg methods and tools that are well known m the art, and performed under aseptic conditions with at least some local or general anesthesia administered to the subject Removal and or replacement of drug delivery devices can also be accomplished using tools and methods that are readily available

M6G can be delivered to an mtracerebrospinal site of the subject accordmg to the method of the invention for any desired period of time In general, mtracerebrospmal admmistration of

M6G can be sustained for several hours, to several days, to several months or years (e g , delivery can be chronic, as opposed to smgle-dosage bolus injection) Typically, delivery can be continued for a period ranging from about 1 month to about 12 months or more This extended peπod of drug delivery is made possible by the ability of the invention to provide both therapeutic benefit (e g , relief from symptoms associated with a condition, e g , pam relief), while avoidmg the onset or seventy of side effects that can be associated with conventional methods of long-term mtracerebrospmal drug delivery, particularly long-term delivery of an opioid analgesic

Side effects that can be avoided or mitigated by mtracerebrospmal delivery according to the methods of the invention include those associated with cytotoxicity of the drug or other drug formulation component, nausea, vomiting, confusion, respiratory depression, constipation, urmary retention, etc ) In addition, the methods and devices of the invention can also serve to mitigate side effects associated with delivery of any drug formulation (e g , side effects associated with disturbance of the tissues at the site of implantation, with disturbance at the site of drug delivery, fluctuations in CSF volume due to the volume of drug formulation delivered or leakage of CSF (e g , spinal headaches) etc ) The mitigation or avoidance of the latter types of side effects can be attributed at least m part to the small dimensions of the drug delivery catheter and to the low mass dose and/or low volume delivery rate used to accomplish drug delivery to the CNS For example, smce the invention can be carried out with low volumes of drug and small diameter catheters, the πsk of mcidence of spinal headaches is diminished The actual dose of M6G delivered will vary with a vanety of factors including physical charactenstics of M6G and the manner in which it is formulated for delivery (e g potency, etc ), the mtracerebrospmal delivery site, the condition to be treated, etc For example, mtrathecal delivery of M6G can be accomplished at a rate of, for example, from about 0 02 μg/hr to about 5000 μg/day, or about 0 02 μg/hr to about 200 μg/hr Appropnate amounts of drug to be delivered can be readily determined by the ordinarily skilled artisan

Delivery of M6G according to the invention can be accomplished usmg a drug delivery device attached to a catheter The distal end of the catheter is implanted at the mtracerebrospmal delivery site The proximal end of the catheter is attached to the drug delivery device to allow for flow of drug from a drug reservoir of the drug delivery device to the catheter distal end adjacent the selected mtracerebrospmal delivery site In one embodiment, the drug delivery is an external or implanted pump, with an implanted pump being preferable Use of such drug delivery devices provides at least the following additional advantages (1) the therapeutic effect of the drug can be provided m a chronic or continuous fashion (e g , for a relatively long peπod of time, e g , hours to days), (2) drug can be delivered to the subject in a smooth and consistent fashion (e g , the bolus effect is substantially avoided, e g , both at the initiation of therapy and/or throughout the preselected period of therapy), (3) the potential for misuse or abuse of the drug is substantially diminished (e g , decreased nsk of dependency, no or little access to a suφlus of drug, etc ), (4) the nsk of overdosing and resulting toxic reactions are decreased (e g , nsk of overdose due to patient or health professional eπor during admmistration is avoided), and (5) patient compliance is increased (e g , the device ensures that drug is continually administered throughout the preselected therapeutic peπod)

Drug delivery devices, catheters, conditions susceptible to treatment, and formulations suitable for use in the present invention are described in further detail below

DRUG DELIVERY DEVICES AND CATHETERS

Any of a vanety of drug delivery devices and catheters can be used m the present invention to accomplish delivery of a drug accordmg to the invention Controlled drug release Devices

Any of a vanety of drug delivery devices are suitable for use in the present invention In general, the drug release devices suitable for use in the invention compπse a drug reservoir for retaining a drug formulation The drug delivery device can be selected from any of a variety of drug release devices that are conventionally used as an external element (e g , an external pump) or implanted element of a drug delivery system In a prefened embodiment, the drug release device is a controlled drug release device The term "controlled drug release device" is meant to encompass any device that provides for controlled release of a drug or other desired substance, and that can be adapted for use in the methods and devices of the invention, e g , a drug delivery device that provides for controlled release of drug through a catheter to a selected delivery site, and at a rate that is suitable to accomplish delivery of a therapeutically effective amount of drug to a treatment site according to the methods of the invention Exemplary drug release devices suitable for use with the drug delivery devices can be based on either diffusive systems (e g , electrodiffusion systems, electroosmotic systems, erosion-based systems, and the like) or convective systems (e g , electromechanical pumps, osmotic pumps, vapor pressure pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps, and the like)

Controlled release of drug from the drug delivery device reservoir can be accomplished in any of a vanety of ways according to methods well known in the art, e g , by incoφoration of drug into a polymer that provides for substantially controlled diffusion of drug from withm the polymer, use of an osmotically-dπven device, etc Drug can be delivered from the drug delivery device and through the drug delivery catheter to the delivery site as a result of capillary action, or as a result of diffusion or convection

In one embodiment, the drug release device is a controlled drug release device m the form of an osmotically-dπven device Preferred osmotically-dπven drug release systems are those that can provide for release of drug in a range of rates of from about 0 01 μl/day to about 100 μl/day (e g , from about 0 0004 μl/hr to about 4 μl/hr), preferably from about 0 04 μl/day to about 10 μl/day, generally from about 0 2 μl/day to about 5 μl/day, typically from about 0 5 μl/day to about 1 μl/day In one embodiment, the volume/time delivery rate is substantially constant and at a substantially consistent rate (e g , delivery is generally at a rate ± about 5% to 10% of the cited volume over the cited time penod, e g , a volume rate of about 10 μl/day is accomplished by delivery of about 800 μl/hour over a period of 24 hours, with the delivery rate over that 24 hours period fluctuating over that period by about ± 5% to 10%) Exemplary osmotically-dnven devices suitable for use m the invention mclude, but are not necessarily limited to, those descπbed in U S Pat Nos 3,760,984, 3,845,770, 3,916,899, 3,923,426, 3,987,790, 3,995,631 , 3,916,899, 4,016,880, 4,036,228, 4,111,202, 4,111,203, 4,203,440, 4,203,442, 4,210,139, 4,327,725, 4,627,850, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,234,692, 5,234,693, 5,728,396, and the like In one embodiment the controlled drug release device is an osmotic pump, e g , an osmotic pump similar to that described in U S Pat No 5,728,396 In one embodiment of particular interest, the osmotic pump is a DUROS™ osmotic pump Drug delivery catheter

The catheter used m the drug delivery system suitable for use m the invention is generally an elongate, substantially hollow structure having a proximal end associated with the drug delivery device of the drug delivery device, and a distal end for delivery of M6G to a desired delivery site The proximal end of the catheter is associated with or attached to the drug delivery device so that drug in the drug reservoir of the delivery device can flow from the drug delivery device, mto and through the catheter, and out the distal catheter end adjacent the mtracerebrospmal delivery site The drug delivery catheter compnses a lumen having a diameter that can be equal to, or can be greater or less than, the diameter of the drug delivery device onfice that serves as a drug reservoir outlet, with the proviso that the catheter is attached in a manner that avoids leakage of drug out of the drug delivery system Where the drug delivery device dispenses drug by convection (as in, e g , osmotic drug delivery systems), the orifice size as well as the size of the lumen of the drug delivery catheter leading from the reservoir of the drug release system can be designed as described by Theeuwes (1975) J Pharm Set 64 1987-91 The catheter body can be of any of a vanety of dimensions and geometnes (e g , curved, substantially straight, tapered, etc ), that can be selected according to their suitability for the intended mtracerebrospmal delivery site The distal end of the catheter may provide a distinct opemng for delivery of drug or a plurality of openmgs The outside diameter of the catheter body can be of a variety dimensions, for example in the range of from about 0 1 mm to 6 mm, usually bemg in the range from about 0 125 mm to about 1 mm The catheter body will define an inner lumen that can likewise be of a variety of sizes, for example having an inner diameter m the range of from about 0 005 mm to 5 mm, usually being m the range from about 0 025 mm to 1 mm, with catheters having larger outside diameters usually having larger lumen diameters

The catheter may be produced from any of a vanety of suitable, substantially impermeable materials Exemplary catheter body materials include, but are not necessanly limited to, polymers, metals, glasses, polyolefins (high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), polypropylene (PP), and the like), nylons, polyethylene terephtholate, silicones, urethanes, liquid crystal polymers, PEBAX™, HYTREL™, TEFLON™, perflouroethylene (PFE) perflouroalkoxy resms (PFA), poly(methyl methacrylate) (PMMA), multilammates of polymer, metals, and/or glass, nickel titanium alloy (e g , NlllNOL™), and the like The catheter can comprise additional matenals or agents (e g , coatings on the external or internal catheter body surface(s)) to facilitate placement of the catheter and/or to provide other desirable charactenstics to the catheter For example, the catheter inner and/or outer walls can be coated with silver or otherwise coated or treated with antimicrobial agents, thus further reducing the nsk of infection at the site of implantation and drug delivery

In one embodiment, the catheter is pnmed with a drug-compπsmg formulation, e g , is substantially pre-filled with drug prior to implantation Pnmmg of the catheter reduces delivery start-up time, e , time related to movement of the drug from the drug delivery device to the catheter distal end This feature is particularly advantageous in the present invention where drug is delivered at relatively low volume rates

CONDITIONS AMENABLE TO TREATMENT BY INTRACEREBROSPINAL DELIVERY OF M6G In general, the invention can be used to administer M6G to manage and/or alleviate pam associated with any of a wide vanety of disorders, conditions, or diseases, generally those associated with opioid-responsive pain Of particular interest is the treatment of disorders, conditions, and diseases associated with chronic pain (e g , chronic pam associated with cancer, physical injury, etc ) Any of a variety of chronic pain patients can be treated accordmg to the invention Causes of chronic pam may be identifiable or unidentifiable Where identifiable, the oπgm of pam may be, for example, of malignant, non-malignant, infectious, non-infectious, or autoimmune oπgm Of particular mterest is the management of chronic pam associated with disorders, diseases, or conditions that require long-term therapy, e g , chronic and/or persistent diseases or conditions for which therapy involves treatment over a peπod of several days (e g , about 3 days to 10 days), to several weeks (e g , about 3 or 4 weeks to 6 weeks), to several months or years, up to includmg the remaining lifetime of the subject Subjects who are not presently suffeπng from a disease or condition, but who are susceptible to such may also benefit from prophylactic pain management using the devices and methods of the invention, e g , pπor to traumatic surgery or concomitant with cancer therapy Chronic pain amenable to therapy according to the invention may involve prolonged episodes of pam alternating with pain-free intervals, or substantially unremitting pain that vanes m seventy

In general, chronic pain can be somatogemc, neurogemc, or psychogemc Specific examples of conditions, diseases, disorders, and origins of chronic pam amenable to management accordmg to the present invention include, but are not necessarily limited to, cancer pain (e g , metastatic or non-metastatic cancer), chronic inflammatory disease pam, neuropathic pain, postoperative pam, latrogenic pam (e g , pam following mvasive procedures or high dose radiation therapy, e g , involving scar tissue formation resulting in a debilitating compromise of freedom of motion and substantial chronic pam), complex regional pam syndromes, failed-back pain (chrome back pain), soft tissue pam, joints and bone pam, central pam, injury (e g , debilitating mjuπes, e g , paraplegia, quadπplegia, etc , as well as non-debilitating injury (e g , to back, neck, spme, joints, legs, arms, hands, feet, etc )), arthritic pain (e g , rheumatoid arthπtis, osteoarthntis, arthntic symptoms of unknown etiology, etc ), hereditary disease (e g , sickle cell anemia), infectious disease and resulting syndromes (e g , Lyme disease, AIDS, etc ), chronic headaches (e g , migranes), causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, denervation, and the like Chronic pain can be associated with any portion(s) of the body, e g ,the musculoskeletal system, visceral organs, skm, nervous system, etc Specific examples of cancers that can be associated with chronic pain (due to the nature of the cancer itself or therapy to treat the cancer) include, but are not necessanly limited to lung cancer, bladder cancer, melanoma, bone cancer, multiple myeloma, brain cancer, non-Hodgkms lymphoma, breast cancer, oral cancers, cervical cancer, ovarian cancer, colon cancer, rectal cancer, pancreatic cancer, dysplastic nevi, endocπne cancer, prostate cancer, head and neck cancers, sarcoma, Hodgkms disease, skm cancer, kidney cancer, stomach cancer, leukemia, testicular cancer, liver cancer, uterine cancer, and aplastic anemia Certain types of neuropathic pam can also be amenable to treatment according to the invention

Chronic back pain, which is also amenable to management usmg the methods of the invention, is another broad category of chronic pam that can be alleviated by application of the methods of the invention Chronic back pain is generally due to one or more of the following six causes (l) stress on lntervertebral facet jomts, caused by slippage, arthntis, wedgmg, or sco osis, (n) radiculopathy, the mechanical compression of the nerve root due to bulging discs or tumors, (m) tendomtis or tendon sprain, (IV) muscle spasm or muscle sprain, (v) ischemia, a local insufficiency in circulatory flow, and (vi) neuropathy, damage to nervous tissue of metabolic etiology or ansing from cord tumors or central nervous system disease

The methods of the invention can be used to manage chronic pam m patients who are opioid naive or who are no longer opioid naive "Opioid naive patients" are those who have not received long-term opioid or opioid denvative therapy for pam management "Non-opioid naive patients" are those who have received short-term or long-term opioid therapy For example, patients who expeπenced intractable adverse side effects with opioids or opioid denvatives conventionally administered by an oral, intravenous, epidural, mtrathecal, transdermal, subcutaneous, rectal, or lnhalational route may be effectively treated delivery of M6G when administered ntracerebrospinally at the dose ranges and/or low volume rates descπbed herein M6G, M6G DERIVATIVES AND FORMULATIONS THEREOF

Methods for isolation of or manufacture of M6G, as well as methods of isolating or manufacturing bioactive M6G derivatives are well known in the art For example, processes for making M6G or substituted M6G are descπbed m U S Pat Nos 5,977,326, 5,621,087, and 5,750,381, as well as m WO 93/03051 Enzymatic processes for making M6G or substituted M6G are described in U S Pat No 5,750,381

The invention also contemplates mtracerebrospmal administration of bioactive deπvatives of M6G Methods of making such bioactive M6G deπvatives are descπbed in, for example, U S Patent No 5,977,326 M6G can be provided as a base and/or pharmaceutically acceptable salt The pharmaceutically acceptable salt embraces the inorganic and the organic salt Representative salts include a member selected from the group consisting of hydrobromide, hydrochlonde, mucate, citrate, succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate monobasic, acetate tπhydrate, bι(heplafluorobutyrate), maleate, bi(methylcarbamate), bi(pentafluoropropionate), mesylate, bι(pyndιne-3-carboxylate), bι(tnfluoroacetate), bitartrate, chlorhydrate, fumarate and sulfate pentahydrate

M6G for delivery accordmg to the invention can be provided m any of a vanety of formulations compatible with mtracerebrospmal delivery The concentration of M6G m the formulation can vary from about 0 1 wt % to about 50 or 75 wt % The drug can be provided in any form suitable for mtracerebrospmal administration, e g , solid, semi-solid, gel, liquid, suspension, emulsion, osmotic dosage formulation, diffusion dosage formulation, erodible formulation, etc Of particular interest is the administration of drug in an form suitable for admmistration usmg an external or implanted pump, particularly an implanted pump, more particularly an osmotic dosage form suitable for use with an osmotic pump Pharmaceutical grade organic or inorganic earners and/or diluents suitable for mtracerebrospinal delivery can be mcluded in the formulations of the invention Such physiologically acceptable earners are well known in the art Exemplary liquid earners for use in accordance with the present invention are sterile aqueous solutions that contain no mateπals other than the active ingredient and water, or may contain a buffer such as sodium phosphate at physiological pH value, physiological salme or both (/ e , phosphate-buffered salme) Suitable aqueous earners may further comprise more than one buffer salt, as well as other salts (such as sodium and potassium chlorides) and/or other solutes The formulations compnsmg M6G for mtracerebrospmal delivery and suitable for admmistration according to the invention may comprise additional active or inert components that are pharmaceutically acceptable and compatible with the active ingredient Suitable excipients can comprise dextrose, glycerol, alcohol (e g , ethanol), and the like, and combinations of one or more thereof with vegetable oils, propylene glycol, polyethylene glycol, benzyl alcohol, dimethyl sulfoxide (DMSO), organics, and the like to provide a suitable composition In addition, if appropnate and/or desired, the composition can compnse hydrophobic or aqueous surfactants, dispersing agents, wetting or emulsifying agents, isotonic agents, pH buffermg agents, dissolution promoting agents, stabilizers, antiseptic agents and other typical auxiliary additives employed in the formulation of pharmaceutical preparations

The formulations for delivery according to the invention can compnse additional active ingredients For example, the formulation can comprise an opioid antagonist (e g , to further decrease the possibility of addiction or dependence, see, e g , an exemplary osmotic dosage formulation compnsmg an opioid agonist and an opioid antagonist is descπbed m U S Pat No 5,866,164

The invention as shown and descnbed is considered to be the one of the most practical and preferced embodiments It is recognized, however, that the departures may be made therefrom which are withm the scope of the mvention and that obvious modifications will occur to one skilled in the art upon reading this disclosure

Claims

What is claimed is

1 A method for management of pam in a subject, the method compnsmg the steps of administering in a patterned fashion a therapeutically effective amount of moφhιne-6- glucuronide or a denvative thereof to an mtracerebrospmal delivery site in a subject, wherein said administering is effective to alleviate pain m the subject

2 The method of claim 1 , wherein said administering is substantially continuous

3 The method of claim 1 , said admmistenng is by use of a catheter compnsmg a proximal end and a distal end, wherein said catheter distal end is surgically implanted at a site adjacent the mtracerebrospinal delivery site and the catheter proximal end is coupled to a drug delivery device, and wherein the drug delivery device delivers moφhme-6-glucuronιde through the catheter and to the mtracerebrospinal delivery site

4 The method of claim 3, wherein the drug delivery device is implanted in the subject

5 The method of claim 1 , wherem the mtracerebrospmal site is an mtraspinal site

6 The method of claim 5, wherein the mtraspmal site is an mtrathecal site

7 The method of claim 5, wherein the mtraspinal site is an epidural site

8 The method of claim 1 , wherein the mtracerebrospmal site is an mtracerebroventπcular

9 The method of claim 1 , wherein said administering is at a low volume rate

10 The method of claim 9, wherem the low volume rate is from about 10 nl/day to about 1 ml/day

11 The method of claim 1 , wherem said administering is for a penod of at least about 12 hours 12 The method of claim 1 , wherein pam m the subject is selected from the group consisting of metastatic cancer pam, non-metastatic cancer pam, chrome inflammatory disease pam, neuropathic pam, post-operative pam, latrogemc pam, complex regional pam syndromes, chronic back pam, soft tissue pain, joint and bone pam, central pain, accidental injury, arthntic pam, hereditary disease pam, infectious disease pain, chrome headache, causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, and denervation

13 A method for management of pam in a subject, the method compnsmg the steps of administering a therapeutically effective amount of moφhme-6-glucuromde to an mtracerebrospinal delivery site in a subject, said administering being at a low volume rate, wherein said administering is effective to alleviate pam in the subject

14 The method of claim 12, said administering is by use of a catheter compnsmg a proximal end and a distal end, wherein said catheter distal end is surgically implanted at a site adjacent the mtracerebrospinal delivery site and the catheter proximal end is coupled to a drug delivery device, and wherem the drug delivery device delivers moφhιne-6-glucuromde through the catheter and to the mtracerebrospmal delivery site

15 The method of claim 14, wherem the drug delivery device is implanted m the subject

16 The method of claim 13, wherein the mtracerebrospmal site is an mtraspmal site

17 The method of claim 16, wherem the mtraspmal site is an mtrathecal site

18 The method of claim 16, wherem the mtraspmal site is an epidural site

19 The method of claim 13 , wherem the mtracerebrospmal site is an lntracerebroventncular site

20 The method of claim 13 , wherem said administenng is patterned

21 The method of claim 20, wherem said administering is substantially continuous 22 The method of claim 13, wherein the low volume rate is from about 10 nl/day to about 1 ml/day

23 The method of claim 13 , wherem said administenng is for a peπod of at least about 12 hours

24 The method of claim 13, wherem pam m the subject is selected from the group consisting of metastatic cancer pam, non-metastatic cancer pam, chronic inflammatory disease pain, neuropathic pam, post-operative pain, latrogemc pam, complex regional pam syndromes, chronic back pam, soft tissue pam, joint and bone pain, central pain, accidental injury, arthntic pam, hereditary disease pain, infectious disease pain, chrome headache, causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, and denervation

25 A method of treating a subject suffenng from chronic pam amenable to treatment by mtracerebrospmal delivery of moφhιne-6-glucuronιde or a denvative thereof , the method compnsmg the steps of implanting a distal end of a catheter at an mtracerebrospmal site in a subject, couplmg a proximal end of the catheter to a drug delivery device to provide a delivery pathway from the drug delivery device, through the catheter proximal end, through a lumen of the catheter, and out the catheter distal end, and delivering moφhme-6-glucuromde or a denvative thereof from the drug delivery device and to the delivery site, wherein moφhιne-6-glucuronιde is delivered to the mtracerebrospmal delivery site m an amount effective to treat pain m the subject

26 The method of claim 25, wherem the drug delivery device is at least partially implanted

27 The method of claim 25, wherem the mtracerebrospmal site is an mtraspmal site

28 The method of claim 27, wherem the mtraspmal site is an mtrathecal site

29 The method of claim 27, wherem the mtraspmal site is an epidural site 30 The method of claim 25, wherem the mtracerebrospmal site is an lntracerebroventncular site

31 The method of claim 25, wherein moφhme-6-glucuromde is delivered at a low volume rate

32 The method of claim 31 , wherein the low volume rate is from about 0 01 μl/day to 1 ml/day

33 The method of claim 25, wherem said delivering is patterned

34 The method of claim 33, wherem said delivering is substantially continuous

35 The method of claim 25 , wherem said administering is for at least about 12 hours

36 The method of claim 25, wherem chrome pam m the subject is selected from the group consisting of metastatic cancer pain, non-metastatic cancer pam, chrome inflammatory disease pam, neuropathic pam, post-operative pain, latrogemc pam, complex regional pain syndromes, chrome back pam, soft tissue pain, jomt and bone pam, central pam, accidental mjury, arthntic pam, hereditary disease pam, infectious disease pa , chrome headache, causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, and denervation