PT98542A - Process for preparation of compositions for the distribution of drugs to a patient's central nervous system, based on cyclodextrin complexes - Google Patents

Abstract

The present invention relates to the process for preparation of compositions for the distribution of a drug to a patient's central nervous system, which involves complexing a drug active in a patient's central nervous system with a cyclodextrin, said cyclodextrin including at least one substituent selected from the group consisting of -OCH3, -ROH-RSO3H, -CO2R, -NHR, -NR2, -NROH and -SiR3, where each R is selected independently from C1-10 alkyl groups which can be straight, branched or cyclic.

Description

72 972 UCAL-1-S759

MEMORY ..... DESCRIT.IV

Field ..... Technical

This invention relates to compositions and methods for administering drugs to the central nervous system of a patient.

Background of the invention

From a therapeutic point of view, a large number of drugs are employed by their action on the central nervous system. Examples of such classes of agents are centrally acting analgesics, antineoplastic agents, cerebral ischemia protectors and compensatory therapeutic agents for central disorders such as Alzheimer's or esquiaorrenia. Other examples include drugs targeting a variety of The intravenous / epidural administration of the centrally acting drugs described above has been shown to have considerable therapeutic efficacy in the treatment of various conditions including pain, spasticity, tumors and infections of the central nervous system. In particular, epidural administration of opioid analgesics represents an important clinical tool for the treatment of acute and chronic pain states Yaksh, T. L. Noueihed, R.Y., Durant, P.A.C .: Anesthesioloav 64: 54-66 (1986). The drug most frequently employed is morphine. Its kinetics are characterized by slow onset and prolonged residence time in cerebrospinal fluid (CSF)

Suffentanil and other anilinopiperidines may be important alternatives to morphine, in this way. These are potent mu opioid receptor agonists that appear to have an intrinsic efficacy greater than. of the Morphine Stevens, G.W., Yaksh T.L.: J. Pharmacol ............ Exp ........... Thsre. 250: 1-8 (1989) and have higher partition coefficients in lipids, indicating that these drugs will have a rapid onset of action »

/ 2 972 UCAL ™ 1 ™ 5759

Centrally, the administration of centrally acting drugs to the central nervous system has some disadvantages. The more problematic is the fact that these drugs can also reach significant plasma concentrations after administration. For example, epidurally administered drugs have several routes of administration. redistribution: (a) movement to fat, (b) passage through the dura and 3. to the spinal cord; and more importantly, movement to the thin-walled epidural venous plexus and then to the systemic circulation Yaksh, TL .: Pain in press 11: 293-346 (1981). Thus, following spinal administration of sufentanil or alfentanil, there are important blood concentrations of opioids earlier, which corresponds to a rapid outflow of the drug from the epidural space Sabbe, MB,

Yaksh, T. L.: J ........... Pain ........ and ........ Svmp .________ Manaq. (1990). This vascular redistribution clearly results in powerful and acute supraspinal side effects. Such side effects are often severe and sometimes fatal.

A key object of the present invention has been to provide improved processes which will allow the regular, acute and chronic administration of agents to the central nervous system via intraventricular, epidural, intra-tecral, iritracisternal and related pathways (hereinafter referred to whole as central nervous system pathways) without the redistribution problem described above. An ideal therapeutic modality requires: (a) the prolonged and predictable presence of therapeutic concentrations of drugs administered to the central nervous system at or near their sites of action in the spinal cord or in the brains (b) limiting the distribution of the drug at the site of desired action within the CNS (ie, minimization of its movement into the vasculature); and (c) the availability of a vehicle permitting the distribution of large concentrations of drugs in relatively small volumes. Typically, drug delivery via the central nervous system may be limited by its relative solubility in water or lipids and / or fsetors which govern their kinetics and render them less than fully effective. Thus, agents with high partition coefficients in iipids can

/ 2 9 /: UCAL ~ i ~ 5759 require unusual vehicles that are not usually biocompatible. Similarly, such lipophilic agents may be immediatly very rapidly upon administration to the central nervous system by giving them a short residence time in the spinal or cerebral tissue and leading to unacceptably high plasma or tissue peripheral concentrations. These characteristics may lead to the failure of a particular drug or significantly limit its utility. The development of a vehicle may alter the speed. which agents may undergo redistribution, render the agent soluble, maintain its bioavailability, and be compatible with the central nervous system of a patient would be of particular importance.

The inventors are the first to recognize that problems associated with administration to the central nervous system of drugs can be improved by administering a drug or drugs to a patient's central nervous system in the form of a complex between the drug and an edeodextrin. eieiodextrin with other types of drugs and / or other routes of administration have been previously known. For example, U.S. Patent 4,869,904 is directed to a " sustained release of an inclusion complex between a drug and an edeodextrin derivative. Administration to the central nervous system of these prior complexes has not been described. In contrast to this prior work, the present inventors have found that complexes between cyclodextrins and drugs, when administered to the central nervous system of a patient, may, inter alia, reduce or delay the diffusion or passage of drug to the vasculature of a patient and, in some cases, increase the efficacy of the drug. drug in ..... alive.

Pitha, JL, et al., Life Sciences, 43: 493-502 (1988), discusses the use of edeiodextrin derivatives to dissolve drugs. In part of this communication, it describes the intracerebral ingrowth of an alkyliodine derivative compounded with alkylating pindolol. In contrast to the present invention, the alkylating pundolol is not a therapeutic drug, therefore its

The cyclodextrin complex is not a complex cyclodextrin complex, as used herein, important, this reference does not disclose any advantages in the administration of a cyclododextrin complex to the central nervous system of a patient

Another prior publication of interest, Kawasaki, A., et al. Pharmacokinetics 3: 61-63 (1974), discusses pharmacological studies on β-cyclodextrin cyathate compounds with prostaglandin E2. In this work, the prostaglandin molecule has been administered to animals by a variety of routes, including a. However, these authors concluded that β-cyclodextrin did not show any effect on their system. It is important to note that the cyclodextrins used to form drug complexes for these purposes should be derived in relation to the parent cyclodextrin as The cyclodextrin molecule used in this prior publication was not substituted. The inventors are not aware of any prior descriptions of the administration of complexes between drugs and cytidodextrins substituted to the central nervous system of a patient as described in more detail below. ,

Summary of the invention

Nerve complexes when present inventors have found that administration of s between substituted cytidodextrins drugs to the central system of a patient provides superior results; compared to the administration of the drug alone. The cyclodextrins of the present invention have hydrophilic and internally hydrophobic exteriors and are capable of forming complexes with a variety of drugs active in the central nervous system. Administration by this means represents an important way to prevent free drug clearance of the central nervous system or of the epidermal space into the vasculature of the patient and may facilitate the diffusion of the drug into the spinal cord or into the brain, thereby increasing its. availability of specific receptor sites in the central nervous system after administration. (AUC) versus the intrathecal dose of morphine (top chart) or in the presence of several samples. Figure 1 shows the area under measure in a hot (52.5 ° C) lofentanil (lower graph) and administered in saline concentrations of a cyclodextrin

Each point represents the mean of four to eight animals- Note that the Y-axis of the lofentanil and morphine curves are different- Standard error indicators are eliminated for clarity. By one-way ANOVA and subsequent Newman Keuls statistical tests. the effects are ranked (p < 005) observed at the highest dose of 2% lofentanil, 0.02%, ordering at 20%, 0.002%, saline; for morphine the dose of 10 micrograms is 0.01%, 20%, 0.002%, 2%, saline. Figure 2 shows the respiratory depressant effects of the epidural treatments with increasing percentage in the C0: ; in ventilation per minute (upper row); percentage change in the thermal pain threshold (middle row) and drug concentrations in the lumbar and cisternal cerebrospinal fluid (CSF) (lower row) in a dog in which the first injection was alfentanil (400 micrograms) in saline solution (left column) and the second injection (given 7 days later) was alfentanil (400 micrograms) in 20% cyclodextrin (right column). Figure 5 shows the sufinganii's dura- meningeal permeability (left chart) or alfentanil (right graph) incorporated into cyclodextrin as a function of time. Each point represents the accumulated amount (mass) of alfentanil or sufentanil which diffused through the samples of total meninges (durations of arachnoid pericardium) of the monkey spinal cord) over time - The slopes of the lines represent 72 972 UCA Lv " 1w'5759 " 1 " meningeal flow. The filled circles are the data for alfentanil or sufentanil dissolved in CSF artificial, open circles are the results with alfentanil or sufentanil in 20% CDEX. The result using meninges isolated from the spinel macula of the macaques indicates that formation of the cyclodextrin complex with opioids may be useful to control the availability of the analgesic drugs for meningeal transfer.

Detailed description ..... ..... ..... realizations ... Preferred

According to the present invention, it has now been recognized that many of the problems associated with administration of drugs to the central nervous system to patients can be resolved or minimized by administering the drugs in the form of cyclodextrin complexes. For the purposes of the present invention, unsubstituted cyclodextrins, i.e., those which have not been modified with substituents, are not at least partly desirable because they are more likely to crystallize or precipitate from the solution in ... ..vivo.

In general, the cyclodextrins are cyclic compounds having a cylindrical molecular structure wherein the inner surface 3 of the outer surface is different in its hydrophilic or lipophilic nature, thus allowing other molecules, known as " invoked molecules " of suitable dimensions, or parts thereof, to penetrate into the intramolecular cavity of the inner part of the " host molecule " of cylindrical cylindrical, thus forming an inclusion complex. In some cases, the drug may form a complex with cyclodextrin at a site other than the intramolecular cavity of cyclodextrin. The two types of complexes are contemplated to form part of the present invention. For most drug-cyclodextrin combinations, the inclusion complex will be the predominant or single complex formed; Thus, inclusion complexes are generally preferred for the purposes described herein.

72 972 U C A L 1 - 5759 -8-

To be useful with respect to the present invention, a cyclodextrin molecule must be capable of forming a complex with a drug of interest and either the cyclodextrin. and the inclusion complex should be compatible with administration to the central nervous system. In structural terms, the cyclodextrin which may be used with respect to the present invention is a. composed of saccharide moieties joined to form a cylindrical structure having an intramolecular bonding cavity. The saccharide moieties may be any of those which can be coupled together either directly or through molecular linkers to form structures which are capable of binding to a drug for administration to the central nervous system - " natural cyclodextrins " well-known are comprised of D-glucopyranose linked to each other by 1,4-linkers. Any of these compounds are useful for the purposes of the present invention when derived as further discussed below. Typically, these preferred compounds will consist of seven or eight molecules of D-glucopyrosis. These cyclodextrins are referred to in the art as alpha, beta and gamma cyclodextrins respectively '

It is well known that some types of cyclodextrins are capable of crystallizing in vivo, thus interfering with the normal processes, and may lead to. damage or renal failure. See, for example, Pitha, J. et al. Life Sciences, 43: 493-502 (1988); (1986); and Pitha, JL Neurotransmission 1, 5: 1-4 (1989), each of which is incorporated herein by reference. Cyclodextrin molecules which rapidly crystallize or precipitate from the solution in vivo are not useful for the present purposes. To avoid this problem, the cyclodextrins of the present invention must be derived when compared to the molecules of cyclodextrin progenitors ,. Thus, for example, with respect to the alpha, beta and gamma cyclodextrins, these parent molecules must be modified with substituents so as to prevent or interfere with their crystallization or precipitation from the solution, especially under in vivo conditions.

The degree and manner of derivatization of cyclodextrin is not specifically limited except that it should be sufficient to minimize the problems mentioned above. The substituents are preferably hydrophilic so as to render the cyclodextrin more soluble in water. In addition, the cyclodextrin is preferably non-symmetrically and incompletely substituted, which reduces its crystallinity. The substituents according to the invention are preferably selected from -OC,, R OH, R OH, . w "COO R" -NHR, -NR '

-NROH > iR " Independently selected from the group consisting of:

where each R is C1-6 alkyl which may be linear, branched or cyclic. Particularly preferred substituents are -OCH3 -ROH. Where possible, the pharmaceutically acceptable salts of the above groups are also encompassed by the present invention.

Each of the saccharide rings in the cyclodextrin may be substituted at the 2, 3 and 6 ring positions. According to the present invention, any one of sites or a combination of sites (for example, 2 and 3, 2 and 6, 3 or 6 and 2 and 3 and 6) may be substituted with one or more of the substituents described herein. For example, in a preferred embodiment, the cyclodextrin molecule will be asymmetrically substituted with B-hydroxypropoxy groups in some but not all of the preferred 2-cyclodextrin moieties. The most preferred cyclodextrin is B-cyclodaxtrin (having 7 g portions) A particularly preferred cyclodextrin is 2-hydroxypropyl-S-cyclodextrin (also referred to herein as CDEX).

Additional specific examples of substituents which may be attached to the saccharide molecules of the cyclodextrins are: hydroxyethyl, hydroxyethyl, hydroxypentyl, hydroxyxy, butylsulfonate, propylacetate, ethylamine, ethylene glycol, and the like.

In addition to the pure substituted cyclodextrins, it is also possible according to the present invention to use mixtures of cyclodextrins. In a specific example of such a

A cyclodextrin (e.g., β-cyclodextrin) is asymmetrically derivatized at less than 100% so that the final composition contains either the parent cyclodextrin or a mixture of cyclodextrins substituted to different degrees by hydroxypropyl groups In this situation, it is useful to note an average degree of substitution of the total cyclodextrin mixture and to define the parent cyclodextrin as being substituted at zero percent and the composition at which each cyclodextrin molecule is substituted at all molecular positions as being substituted to 100%. For these purposes, the preferred degree of substitution ranges from 10% to 100%, the most preferred range being from 15% to 80%. Lower or higher degrees of substitution may be required for particular drugs or for particular types of desired effects in vivo. It is preferred, although it is not thought to be essential in all cases, for the drug to be capable of dissociating itself from the cytoxodextrin complex in vivo so that the free drug is available for its desired pharmacological activity. Theoretical considerations suggest that the rate of dissociation is proportional to several variables, including (a) the stability constant of the drug-cyclodextrin complex; (c) the local concentration of cyclodextrin in the volume in which the complex is distributed. If there is a molar excess of cyclosodextrin, the probability of finding free drug in solution or in the space of the central nervous system is proportionally decreased. In the case of the traditional routes of administration (eg intravenous or oral), the total volume of drug or The microcapsule complex administered is diluted in a large space or volume, essentially infinite. Thus, the amount of cytidodextrin employed may not be critical as long as it is sufficient to bind a significant portion of the available drug and the rate of dissolution of the inclusion complex will be largely dependent on the stability of the complex. On the other hand, if the drug-cyclodextrin complex is administered in a space or volume from which the drug, but not the cyclodextrin, can diffuse rapidly, then the molybdenum excesses of cyclodextrin will be 72 972 UCAL-JL-S759-11 - #

proportionally reducing the rate at which the drug molecule will be free to diffuse, i.e., the free molecules will be in equilibrium with the excess binding sites supplied by the cyclodextrin. Based on this consideration, agents such as cyclodextrin injected into the intrathecal or intraventricular (such as cyclooxygenase-drug) epidural spaces may have optimum concentrations or molar ratios between cyclodextrin and drug for drug delivery, depending on the rate to which the emergence of the free drug is desired. The freedom with which a complexed drug may be withdrawn from the middle of the cyclodextrin cavity is a function of the size of the drug molecule, its form and its solubility. Lipophilic drug molecules, with greater affinity to the hydrophobic interior of the cyclodextrin. If the liposolubility of the drug is too high, the drug may not dissociate at all, even when the complex approaches a lipid membrane? thus, some drugs would become inactive since they would not target specific tissue receptors in an active form. In its simplest form, the interaction between a drug and a cyclodextrin resembles that of a competitive ligand and as such it obeys the law of mass action with affinity proportional to the liposolubility and other physiological properties of the drug Pt ha, J -Meurotransmissions ....... Research

It will be appreciated that increasing the degree of substitution of cyclodextrin will increase the apparent binding affinity of lipophilic drugs to the cyclodextrin molecule. For opioids with high liposolubility, it is expected that a sub-stitch However, for opioids with low lipid solubility, the

For purposes of the present invention, it is a relatively straightforward matter to determine whether a given combination of cyclodextrin and drug is capable of being cleavable in vivo. It is known 7 "? 97 '7, U C A L-1 -5759 " 12

a ligand by means of standard techniques. For example, the interaction between a cyclodextrin and a drug can be studied by equilibrium diaiysis or other suitable techniques. The binding data in equilibrium can be analyzed by a Scatcharc! standard, which allow to quickly calculate the intrinsic dissociation constant of the ligand. Once the dissociation constant for a particular drug / cyclodextrin combination is known, a reasonable estimate can be made as to whether the complex will be dissociable from the live. If the measured dissociation constant is greater than, for example 10-6 H, in vivo dissociation can be expected to not occur to a significant degree or occur at a very low rate. The conditions under which the binding constant is measured may be rendered more similar, to the conditions already present per adjustment, for example of the pH and the concentrations of various ions, etc. Binding constants measured under these conditions may closely approximate the binding constant under in vivo conditions "

It should be noted that a slow dissociation rate does not in theory exclude the utility of the cyclodextrin-drug complex. First, dissociation is based on the law of mass action and if the drug diffuses into a large volume, such as CSF or spinal 1-marrow, then equilibration ooridiÇ © will allow the development of concentrations sustained at steady state. Thus, the ability to define the dissociation constant can be used to predict a priori whether the drug complex will reach a high or low steady state concentration relative to the amount of drug administered. Consequently, it would be possible with this information to build the distribution profile of the drug. Agents with low dissociation rates would be given in large-quantities to achieve a given level of free drug in the appropriate biospace.

A second theoretical consideration mentioned above involves the relative concentrations of drug and cyclodextrin when given in a limited kinetic space. If the drug ratio for UCAL-1-5759 Λ

In other words, the presence of excess unbonded cyclodextrin will represent a reservoir of binding sites that will compete with the tissue. In other words, the presence of excess unbound cyclodextrin will represent a reservoir of binding sites that will compete with the tissue redistribution of the drug. It should be noted that this is different fundamantaimeritis from a systemic route of administration where total (linked and free) cyclodextrin is distributed in an essentially infinite volume (the body vasculature tree) in contrast to the limited, cerebrospinal fluid volume or epidermal space . If too much cyclodextrin is administered with the drug, the drug's activity will be decreased; if too little, then redistribution of the drug into the vasculature will not be sufficiently delayed. Thus, there are three factors that govern in particular the central nervous system redistricting of the drug / cyclodextrin complex: the drug-cyclodextrin complex dissociation constant, the drug / cyclodextrin ratio and the total dose of cyclodextrin administered in the particular space. It will be appreciated that these variables will result in an optimal drug / cyclodextrin dose ratio and an important consideration is the ability to define these races as in vivo / in vivo models. In accordance with this invention, some drug: cyclodextrin complexes will be pharmacologically active even if the drug has not dissociated from the complex. This could occur, for example, if the active moiety of the drug was available for interaction at the target site (e.g., a specific receptor) even though the drug molecule was complexed by the cyclodextrin. A further possibility is that the drug could form a complex with a site on the cyclodextrin molecule different from the intramolecular cavity "ie," on the surface of the cyclodextrin binding of the drug to substituent groups, such as haloid chains Such complexes also form part of the present invention. c icodood r in a can 0 i nte rvatio n

In general, the molar ratio of drug is varied over a relatively large range.

will depend on the particular mode of administration and the drug and cyclodextrins. For epidural administration, the moiety will generally range from about 1:10 to 1: 10,000; for intrathecal and intraventricular administration, the molar ratio will generally range from about 1: 10 to about 1: 1000. These ranges are given to exemplify typical ranges; and will not necessarily apply to the entire drug-cyclodextrin complex with activity in the central nervous system utii

In order to ascertain if a given inclusion complex has active in vivo, standard assays may be employed in .1.0 live ... models such as those exemplified below, such tests will also rapidly provide information on whether there is a deviation in the activity / time curve for a given complex, i.e., in vitro determination of the binding constants between the drug and. and the live measurements of the meningeal flow coupled to results in in vivo models allow, therefore, to determine whether a given complex is active in vivo.

In the development of the use of cyclodextrins as a delivery system to the central nervous system, the inventors employed various in vivo models in which the animal is chronically prepared with intrathecal spinal and / or epidural spinal catheters which allow the non-traumatic injection of different agents of drugs in different vehicles. Using these models, the inventors were able to quantitatively define the effects and characteristics of the distribution of agents given various pathways and to evaluate concurrently a. potential toxicity and kinetics of drug redistribution, pharmacologically and toxicologically * these systems are highly predictable of the effects in human patients.

In some of these preliminary studies, the inventors observed that there were moderate increases in antinociceptive effects for morphine, but a highly significant increase in duration of action for lofentanil following intrathecal administration to a cyclodextrin, when compared to

U C L J L X S7S9 15

a vehicle of saline solution. No evidence of toxicity was observed in these preliminary studies.

In addition to the in vivo studies which demonstrate safety, efficacy and still characterize the role of the composition of the drug-cyclodextrin combinations in kinetics and drug activity, the inventors have also examined the influence of cyclodextrins on particular model drug diffusion rates opioid alkaloids, through live samples i.e. These studies, described in the examples below, may determine the extent to which various concentrations of cyclodextrin can regulate and thereby extend the duration, for example, by increasing the duration of the cyclodextrin. example, of the spinal action of epidural or intrathecal cyclodextrin complexes administered. Thus, these models serve as ex vivo systems allowing the rapid approximation of the cyclodextrin ratio: optimal drug required for the use of the compelling procedure for other spinally administered agents, such as other opioids and agent; The different components of the ex vivo permeable permeability model are useful in predicting the diffusion rates of cyclodextrin complexes from the epidural space to the spinal cord (using the total ligand complex to measure flow), . This ex vivo study allows us to make predictions useful for the concentration of cyclodextrin (" cyclodextrin ratios ") which will provide optimal coagulation actions to provide a prolonged residence time following intrathecal / epidural administration "

Drugs which are useful for the purposes of the present invention are not specifically limited, and they should be capable of forming a complex with a cyclodextrin and must be suitable for administration to the central nervous system of a patient. By " central nervous system " , as used herein. it is meant that it comprises central. This any surface, region or volume of tissues the spinal cord, brain or nervous system would include, for example, the brain within the brain.

UCAL '759 " 1.6 cranial cavity (intraventricular), the spinal canal (epidural) and the space between the arachnoid-mater and the pia mater (intrathecal). From a therapeutic point of view, a large number Typical of such classes of agents are analgesics which act primarily as anti-neoplastic agents, protectors of cerebral ischemia, compensatory therapeutic agents for central disorders such as Alzheimer's or schizophrenia, and other drugs targeting a variety of central nervous system disorders. Cancer chemotherapeutic agents such as methotrexate and busulfan are often employed in cases of tumor involvement in the central nervous system. Methotrexate is often used intrathecally to obtain a high concentration in the system central nervous system agents are employed in the central nervous system to reduce the likelihood of sowing of cerebrospinal fluid as in carcinomatosis meningus. See Kooistra, KL et al., Cancer 46:31, 323 (1986). Combinations of methotrexate and a cyclodextrin could favorably alter the kinetics of redistribution following intrathecal or central nervous system administration. Busulfan, a highly lipophilic agent, is useful for the reduction of central nervous system tumor, but when administered orally it causes a severe depression in the bone marrow, similar to. various other cancer chemotherapeutic agents. Combinations of busulfan with cyclodextrin may allow its use in the central nervous system. Similar advantages can be achieved by a variety of drugs used for non-metastatic syndromes in which concentrations in the central nervous system of drug have proven to be effective. Examples of such cases include fungal infections of the central nervous system and meningeal infections. The distribution of local anesthetics could also be performed in this way. Other conditions that may be treated are: spasticity, convulsive disorders, and araenoiditis. It is likely that in the near future, therapeutic agents for AIDS and for. other virus-mediated conditions can be addressed in this manner by drugs having properties 972 972

UCAL-JL-5759

unfavorable or poor pharmacodynamic agents. Agents such as cyclodextrin could be considerably advantageous in such cases, not only because they provide a useful nontoxic soiling medium but because of their effects on the bioavailability of the drug.

The other drugs which formed the basis for various preliminary tests conducted by the inventors are the opioid analgesics suitable for central administration. Examples of such drugs are as follows; alfentanil »suferitanil» lofentanyl »fentanyl and morphine»

The complexing processes according to this invention may be carried out by any of a number of standard processes known to those skilled in the art. The precise physical process of complex formation is reiatly insignificant for the present invention as long as the complex is formed at the time it is present in the patient's central nervous system. The specific processes that can be used are; the kneading process, the solution process, the lyophilization process or the like '

A preferred process for the production of the complexes for administration to a patient involves the provision of an aqueous solution containing an appropriate amount of a drug to be complexed and a cyclodextrin and allowing the solution to well rest for a suitable period of time ( for example from about 1 hour to about 24 hours or more, to thereby allow the formation of a complex. The aqueous solution which is used to form the complex will generally be the same solution as is used to administer the complex. The cyclodextrin drug complexes will preferably be administered to a patient in a physiologically acceptable medium, such as physiological saline solution containing standard additives for administration to the central nervous system of drugs. Preferred media are; dextrose (for example, 1-5%) in sterile water or sterile water alone. Confirmation of the formation of a drug complex with the cyclodextrin derivative may be carried out by a variety of processes, including powder X-ray diffraction, dissolution behavior, scanning electron microscope analysis, differential thermal analysis and infrared absorption.

The drug-cyclodextrin complexes described above may be administered to patients by standard procedures commonly employed for the administration of the non-complexed drugs. The purpose of such an administration is to provide an effective amount of active drug to the central nervous system of a patient. It is generally appropriate to employ the standard dosages of non-complexed drugs to evaluate the results with a given drug: eiciodextrin complex. However, in some cases, the activity of the drug will be enhanced (e.g., increased potency, increased efficacy, and / or increased duration) by administration as a complex with a cyclodextrin due, for example, to the greater residence time of the active drug at its principal site of action and less supraspinal vascular redistribution or apparent redistribution in the flow. As a result, smaller doses of the compound drug compared to those of the non-complexed drug may prove to be suitable for administration to a patient. The optimum dosage range may be determined using standard animal models and / or clinical trials.

In general, the amount of the complex to be administered should be sufficient to effectively treat the condition to be treated by the physician. Such conditions may include pain caused by a variety of disease and / or injury states, including cancer, pain caused by other stimuli (eg labor pain, post-surgical pain), spasticity, CNS tumors and infections, and a variety of other disease states targeted by the drugs summarized above. An expert will be able to determine the appropriate effective amounts using the standard templates described herein and / or standard pharmacological testing techniques.

Exemplary modes of administration of the above-described drugs include epidurals (administration into the epidural space) or intrathecal (administration into the space containing cerebrospinal fluid); the intracranial (administration in the cerebral parenchyma); or the intraventricular (administration in the cerebral ventricles)

Patients are preferred: animals are also possible. however, veterinary uses are also contemplated for the purposes of the present invention.

In addition to the drug delivery processes, the present invention also encompasses compositions suitable for such administration, which comprise a drug complexed by a substituted cyclodextrin and standard media for administration to the central nervous system of a given drug. standard surfactants or other drugs which do not form complexes but which interact physiologically or pharmacologically with the complexed drug (for example, cyclodextrin: opioid with an agonist such as dexmedetomidine)

The following examples are set forth to illustrate the advantages of the present invention and to assist an expert in the preparation and use thereof. These examples are not in any way intended to limit the scope of the disclosure or protection afforded by the Patent Title > < & numsp & numsp & numsp 1 " Drug Preparation 40%

A 2 (a) (1)

NaticK »MA» The following others; sulfate de was purchased from Research Biochemical Inc agents were obtained from morphine source (Merck); sufentanil citrate; alfentanil, HCl; and lofentanil oxalate (Janssen Pharmaceutica * also known as Janssen Research Foundation),

All drugs were prepared when indicated either at 72 972 UCAL-1-5759

rr * & Sterile saline solution either in cyclodextrin dissolved in distilled water at the indicated percentage. Under these conditions, the heavy drug was dissolved by simple mixing and stirring. The capsaicin was also administered dissolved in dimethylsulfoxide (DMSO; reagent grade, Sigma Chemical) and then brought to the permeability were finely dissolved in brine. In the msningeal studies, drugs with or without cyclodextrin in artificial cerebrospinal fluid, 2 "Toxicity Studies a - I nje c, ç Õ. is ....... l..nt rafc.ee a is ......... lumbar ........ r .......... rats: rats (250-350 g) were prepared with chronic intracellular catheters placed in the lumbar intractal space. They received the intrathecal administration of 15 μΐ of 25% CDEX. There was no change either acute or after 7 days in the motor function of these animals as assessed by the placement / bladder reflexes or bladder function (absence of urine spots on the abdomen). At 7 days, levels of neuropeptide P and peptide related to the calcitonin gene (CefEP) were measured after tissue extraction using radioimmunoassays. Tissue concentrations of these peptides found in non-myelin afferent sensor neurons were not altered when CDEX was administered in the absence of other agents. In contrast, the use of the vehicle dimethylsulfoxide (25% in saline) resulted in a significant reduction in the levels of the two peptides. b "Injections ....... Intratecal ........ lumbar ............... çobaíass The guinea pigs (males 300-400 g; N = i2) was administered 20% CDEX by percutaneous puncture of the lumbar intractal space with a 30 gauge needle "There were no acute signs of behavioral agitation" indicating no irritation. There were no changes in the motor function of the animals as measured by the gait, gait and balance reflexes or outpatient tests. No evidence of urine staining was observed.

The bigle dogs (11-15 kg) ........ epidurals ........ lumbars .......- ...... dogs

72 972 UCAL 5759 prepared with lumbar epidural catheters received 20% CDEX titers (2 ml, a standard volume of injection in this model). This treatment had no effect on heart rate, bladder function, or response of the contraction of the palate for periods up to 7 days after each acute injection. These data indicate the lack of toxicity of spinal CDEX. I n.le c. t a ve n £ r. . The. r e s r. (I.e. Ζ.Ά .D. at. In rat rats prepared with chronic intracerebral ventricular cannulae (ICVT) and electroencephalographic electrodes # 1 CDV injection of CDEX (20%; in a standard volume of 10%) had no effect on general motor behavior or EEG activity for periods up to 7 days after injection. 3. Antinociceptive activity a .. In, section ... ... intratecai ........ "...... xata ^ anasj: ...... ... Meets ".... .... ..... ..... uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma uma concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração concentração .......... ........ of ........ drug.- Rats prepared with intrathecal lumbar catheters were injected with different amounts of morphine # sufentanil # alfentanil or lofentanil. Injections were done in i.v.mu. volumes of saline vehicle or in a 20% CDEX vehicle. For all drugs, there was a shift to the right on the intratecai dose response curve (indicating increased potency) and an increase in the duration of antinociceptive effect. As shown in Table 1, the ordering magnitude increase in potency # decrease in DES0) at this concentration of CDEX was :: alfentanil; lofentanil; morphine; and sufentanil. it is also indicated that with the addition of CDEX there was a significant increase in the area under the analgesia time course curve (indicating an increased duration of action) for each of these four drugs

Table 1

Effect of peak intratecaic 2-hydroxypropyl-1α-cyclodextrin (20%) and duration (AUC) of the antinocíceptive effects in the opioid rat given intrathecally in the hot plate test

Spinal Drug DE50 (Ud) (1) ... AUC-3000 (5!) Saline Solution Li · L Saline Solution CDEX Morphine or Γ. 3 1,1 1,7 0,3 Alfentanil 8; J 2 or H 80 17, Suf eritanii 0, 2 0.06 0. 5 0.2 Lofentanil 0.01 0.02 0.0 , 1) MPEs% of maximal effect possible after hot plate test 2) AUC- area under the time-effect curve calculated using the HPE curve x Time- The value indicated indicates the dose (pg) required to produce a value of arbitrary AUC of 3000s each DE50 value (dose required to produce the maximum effect possible in 50% of the animals) represents the mean of 12-18 rats. All differences between the saline and CDEX groups are statistically significant by test untwisted at the level p < 0 < 05 > b. Intrathecal disorders ........ in ........ rats, ......... effects ..... ... of the change ......... of the concentration of CDEX ......... in the effects ........ spinal ......... .. ........ opioids. The rats prepared as above received a. injection of morphine (3 pg / 10 μg) or iof eritanii (0.1 pg / 10 μg) dissolved in sterile saline solution, with tractions that induced small but measurable analgesic effects. Other prepared rats as above received injections of these cioses at the CDEX concentration of 20%, d. & , 0.01% or 0.02% (as shown in Table 1), the optimum concentration leading to the most significant increase in the antinociceptive γ-analgesic effect) in the hot plate test was 0%. 2¾ for morphine & 2% for iofentanil. Two - sided concentrations of 0.2% for a. morphine and 2% for lofentanil gave progressively smaller effects. U C A L -1 - S 7 5 9

Table 2

Effects of varying cyclodextrin concentrations in the area under the time-effect curves of lofentanil (0.1 pg / 100 μg) or intrathecal morphine (3 pg / 10 μg) in rats. __________ Cyclodextrin Concentration (¾w / v) __________ ................ Vehicle: Saline Solution 0.002 0.02 0.2 2.0 20.0 ....... Intact

Morphine (3 Mg) 46 55 112 30 23 33 (0.1) (0.5) (0.5) (0.9) (0.8) (0.5) Lofentanil (0.1 Mg) The values represent the mean (SE) of the AUC / 100 produced by (a) indicative dose of the opioid at the concentration of CDEX; associated up to 2.0% or saline solution. c .. Effects .......... of ......... CDEX ......... nos ......... effects ..... ..... antinocicePtivQs ......... do ......... alf entanil epidoral ........... in .......... dogs. The dogs were prepared with lumbar epithelial ethers and chronic tracheostomies. Respiratory function curves (ventilation slope per minute (Vej vs. terminal wave of 00λ >) were measured using the '

resuscitation read in a C02 terminal wave range of 4.7 to 10.7 kPa (35 to 80 mmHg) CO. The contraction response of the skin to a thermal stimulus was used to evaluate the nociceptive threshold. 400 pg) administered in saline normally gives a full short duration (< 90 min) nociceptive terminal point (skin contraction response), a significant respiratory depression (reduced V1 vs. CO2 slope), as indicated in Table 3. The

Injection of alfentanil with 20% CDEX did not

In injection of a prolonged analgesia analgesia riem in changes in the respiratory function, the same dose of alfentanil in CDEX to 2% results in FIGURE 2 presents these data ... UCAL-1 ~ 5759 sr

Table 3

Effects of epiduralally administered alfentanil (400 μg) on the nociceptive threshold and the response function to the dog when given in 2% saline or 2% hydroxyl trans-cyclodextrin solution.

Analgesia i 1J Peak MPE Tl / 2 t '% decrease in slope Saline solution E> 79 - 60 min 40 00 EX at 20¾ 26% 40 min 18 2% CDEX 100% ISO min 19 .11 Peak time (mini Expressed as the% of HPEs T1 / 2 expressed as necessary for the effect to decline approximately 50 ° C maximum effect observed after epidural injection of alfentanil (400 μg) (2) values indicate the reduction of the maximum percentage in the response deviation of velocity x volume wave (VS) vs. CO measured using resuscitation techniques 4 "Location and Redistriction a. In.lection .......... int ratecal .......... Following intrathecal injection of various opioids, concentrations of the drug in the spinal cord, forebrain and plasma were evaluated. As indicated in Table 4, the concentrations of drug in the forebrain (indicating the degree of supraspinal redistribution through the vasculature) were significantly reduced after administration. The combination of opioid CDEX in contrast with the observed concentrations when opioids were administered in saline jersey .. ^ 72 972 UCAL-1-c S759 _ :.

Table 4 · / > - * .......-.

Concentrations of intrathecal alfentanil injection in the rat, brain and plasma below. Prosthesis Plasma Time Injured measurement. π g / 1 m. Morphine / Saline solution 411, Morphine / CDEX 5 min 53, 20% 3 min 18, 1140, Lofentanil / Saline solution 5 min 1.78 0 h 96 Lofentanil / 20% CDEX 5 min 0 ϋ 41 0.0 A1f in 1% / saline solution 5 min 146 75.1 aIfentanyl / 0DEX 45 min 104 4, 1 to 20% 5 min X ν ϋ li 8.1.6 45 min 10, 7 0.0

Each value represents the mean of 4-5 rats' b. Effects ........ of ...... CDEX ...... na ....... redistributed ....... dQ ....... aifentaní.l In dogs dogs with epidural catheters as described above, the injection of 400æg of alfentanil in saline resulted in a rapid increase in plasma peak drug concentrations As shown in Table 5, peak plasma concentrations and total body clearance of alfentanil measured with coadministration of 400 μg of alfentanil and 20% CDEX and to a lesser extent 2% χ 2 were markedly reduced. The apparent volume of epidural space (Va) was increased by CDEX. Taken together, these results show that COEX delayed the rate of redistribution of alfentanil from the epidural space to the systemic circulation.

Table 5

Pharmacokinetic parameters in a 3-exponential model measured in lumbar CSF after epidural administration of alfentanil (400 μg) ··

A solution of 2% COEX (a) CDX 2X)% (N-13 Tl / 2abs 1.57 7.2 (3.4) 30.7 (2.2) Tl / 2 to 7.9 7.4 (5.8) 52.3 (7.13 Tl / 2 β fb, .X, and 324, (31.4) 2179, (152) C max 1286, 2259, 1119) 257, (25353 1 max 4.66 10.7 (7.1) ---- * 11/2 abs: absorption half-life (min), TI / 2 air redistillation, Tl / 2 b: half-life of elimination, Cmaxr maximum predicted concentration, Tmax: time (min) of C max *, could not be calculated for CDEX at 20% (a): the value indicates the result of a single animal The values in parentheses represent the value observed in that animal without COEX 5 "Ex vivo Meningeal Diffusion a.Effects of CDEX ........ at speeds of diffusion ......... .... ... opioids from compartments ......... epidurai ......... to ......... ps ._______ compartments ......... in. A diffusion cell was used to measure the meningeal permeability of opioids and other d The live specimens of the total spinal meninges (including hard, pia and arachnoid) were dissected from macaque nematode monkeys, most recently sacrificed; the tissue was set up in a two-temperature controlled diffusion cell and maintained via constant exposure to mechanically stirred artificial CSF (the two surfaces at 37 ° C continuously saturated with Og / Cc). A well (10 ml) of the cell (A) is employed for the addition of al 1 parts of 5 ml of the drug either in CSF or together with various concentrations of CDEX in CSF and simultaneously addition of the solution to the well (A), an equal volume of oxygenated CSF is placed in the other well (.8), followed , minimum volumes (0.2-0.4 ml) of the solution are collected in the well (B) to analyze at regular intervals up to 2-24 hours. As volumes are withdrawn from (B), a volume equal to maintain the volume originally measured. Samples are analyzed by HPLC, (3C-MS) or radiometric methods to measure drug and COEX concentrations that have diffused through the meninges. The slope of the regression line drug concentrations in (B) vs. time is the flow from which the meningeal permeability of that drug is directly calculated "

As an example of flow measurement, alfentanil and sufentanil motions were examined alone (in CSF) and CSF-CDEX at concentrations of 2% or 20% CDEX. The results show that the diffusion rate of these agents is highly modified by the presence of CDEX. The live model also demonstrates the differential effect of CDEX on different drugs. Thus, the degree of reduction in flux meningeal, after complexation with CDEX, is alfentanil > sufentanil (FI8URA 3). "In 20% COEX, there is a 10 and 100-fold reduction for sufentanil and alfentanil, respectively. This CDEX modulations in the meningeal opioid flow shown and the relative changes in flux for the two compounds mirror these increases in analgesia described in the intrathecal injection model in vivo. The extent of modulation of meningeal transfer for these model drugs through the meninges and the spinal cord can be adjusted to achieve optimal epididymal speeds from drug to spinal cord using different (optimal) concentrations (and / or mole ratios) of CDEX in combination with the drug

72 972 UCAL-i-5759 administered. Results with the meningeal model ex ......... live indicate that equivalent variations of CDEX concentrations in CDEX solutions (eg, CDEX at 20 vs, 2 vs. 0.21, etc.) .) have different modeling effects on drugs. As an example, the combinations of alfentanil in 20% CDEX produce a 50 to 100 fold reduction in the meningeal flow (when compared to alfentanil dissolved in C8F) whereas 2x CDEX reduces speed only by 20 times. concentration and probably a function of the molar ratio of the free drug to unoccupied CDEX sites of occupancy,

Although the present invention has been described in connection with preferred embodiments, an expert upon reading the foregoing specification will be able to effect various changes, substitutions by equivalents and changes of the subject matter described herein. Consequently, it is considered that a. The protection afforded by the patent title is limited only by the definitions contained in the appended claims and their claims,

Claims (5)

A method of preparing a composition for delivering a drug to the central nervous system of a patient, characterized in that an active drug is complexed in the central nervous system of a patient with a cyclodextrin , said cyclodextrin comprising at least one subtituyrite selected from the group consisting of -QCH2, -RHR-RSC2 H, -CO2 R3, -NR2 -NR2 H and -NR1 R3, wherein each R3 is independently selected from , from alkyl groups which may be linear, branched or cyclic ' 2. A composition according to claim 1, characterized in that said drug is an analgesic. A method according to claim 2, wherein said analgesic is an opioid. The method of claim 3, wherein said opioid is selected from the group consisting of alfentanil, lofentanil, sufentanil, fentanyl and morphine. characterized 5. A medicament according to claim 1, wherein said drug is an antineoplastic agent. 6. A medicament according to claim 5, wherein said agent is methotrexate or busulfan. Claim 1, characterized in that said drug is a protector of cerebral ischemia. 8. A process according to claim 1, wherein said cyclodextrin is a hydroxy (α-cyclodextrin), according to claim 1, wherein said cyclodextrin comprises six to eight glucose molecules. A process according to claim 1, characterized in that the cyclodextrin is complexed with the drug in a molar ratio of about 10 to about 100,000. For THE REGENTS 0F THE UNIVERSITY OF CALIFORNIA = 0 OFFICIAL AGENT.-