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Title:  Method for treating endocrine disorders

United States Patent:  6,827,931

Issued:  December 7, 2004

Inventors:  Donovan; Stephen (Capistrano Beach, CA)

Assignee:  Allergan, Inc. (Irvine, CA)

Appl. No.:  692811

Filed:  October 20, 2000

Abstract

Methods for treating endocrine disorders and for inhibiting gametogenesis by intracranial administration to a human patient of a therapeutically effective amount of a neurotoxin, such as a botulinum toxin type A.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention meets this need and provides methods for effectively treating a variety of endocrine disorders by intracranial administration of a neurotoxin which has the characteristics of long duration of activity, low rates of diffusion out of an intracranial site where administered and insignificant systemic effects at therapeutic dose levels.

A method for treating an endocrine disorder according to the present invention can comprise the step of intracranial administration of a neurotoxin to a patient, thereby alleviating a symptom of an endocrine disorder. The neurotoxin can be made, for example, by a bacterium selected from the group consisting of Clostridium botulinum, Clostridium butyricum, Clostridium beratt, and Clostridium tetani or can be expressed by a suitable host (i.e. a recombinantly altered E. coli) which encodes for a neurotoxin made non-recombinantly by a Clostridium botulinum, Clostidium butyricum, Clostridium beratti or Clostridium tetani. Preferably, the neurotoxin is a botulinum toxin, such as a botulinum toxin type A, B, C1, D, E, F and G. More preferably, the botulinum toxin is botulinum toxin type A because of the high potency, ready availability and long history of clinical use of botulinum toxin type A to treat various disorders.

The botulinum toxin can be locally administered in an amount of between about 102 units and about 500 units and the endocrine disorder symptom alleviating effect from a local administration of a botulinum toxin according to the present invention can persist for between about 1 month and about 5 years.

Notably, the neurotoxin can be administered to the hypothalamus, such as to the median eminence region and/or arcuate nucleus area of the hypothalamus. Additionally, the neurotoxin can be administered to the pituitary gland, including to the anterior pituitary or posterior pituitary. The intracranial administration step can comprise the step of implantation of a controlled release botulinum toxin implant.

A detailed embodiment of a method within the scope of the present invention for treating an endocrine disorder can comprise the step of intracranial administration of a therapeutically effective amount of a botulinum toxin to a patient, thereby treating a symptom of an endocrine disorder. The endocrine disorders treatable by a method according to the present invention include afflictions which result from an excess of any of the hypothalamic releasing factors or of any of the pituitary hormones, including GnRH, GH, LH and/or FSH. Thus endocrine disorders such as, for example, acromegaly, gigantism, Cushings disease, hypergonadism and hyperthyroidism, can be treated by a method according to the present invention.

A further detailed embodiment of a method within the scope of the present invention for treating an endocrine disorder can comprise the steps of: selecting a neurotoxin (such as a botulinum toxin)with hypothalamic releasing hormone, or pituitary hormone, suppressant activity: choosing a hypothalamic or pituitary target tissue which influences an endocrine disorder; and; intracranially administering to the target tissue a therapeutically effective amount of the neurotoxin selected, thereby treating the endocrine disorder.

A method for treating hypergonadism according to the present. invention can comprise the step of in vivo local administration of a therapeutically effective amount of a botulinum toxin type A to a cholinergically influenced hypothalamic tissue to a human patient, thereby alleviating a symptom of hypergonadism in the patient.

Additionally, a contraceptive method according to the present invention can comprise the step of intracranial administration of a botulinum toxin (such as a botulinum toxin type A) to a patient, thereby reducing an intracranial secretion of a hormone required for gametogenesis. Thus, ovulation can be inhibited by intracranial administration of a botulinum toxin to a patient, thereby reducing an intracranial secretion of a hormone which influences ovulation. Furthermore, sperm production can be inhibited by intracranial administration of a botulinum toxin to a patient, thereby reducing an intracranial secretion of a hormone which influences production.

The neurotoxin can be a modified neurotoxin, that is a neurotoxin which has at least one of its amino acids deleted, modified or replaced, as compared to a native or the modified neurotoxin can be a recombinant produced neurotoxin or a derivative or

I have surprising found that a botulinum toxin, such as botulinum toxin type A, can be intracranially administered in amounts between about 10-2 units to about 500 units to alleviate an endocrine disorder experienced by a human patient. Preferably, the botulinum toxin used is intracranially administered in an amount of between about 10-1 unit and about 50 units. More preferably, the botulinum toxin is administered in an amount of between about 10-1 units and about 5 units. Most preferably, from about 0.01 units to about 10 units of a botulinum toxin type A and from about 0.1 to about 100 units of a botulinum toxin type B is used is a method practiced according to the present disclosed invention. With regard to the other botulinum toxin serotypes (including toxin types E and F) the unit dosage to be used is within the range of about 0.01 units to about 500 units, as set forth herein. Significantly, the endocrine disorder alleviating effect of the present disclosed methods can persist for between about 2 months to about 6 months when administration is of aqueous solution of the neurotoxin, and for up to about five years when the neurotoxin is administered as a controlled release implant.

Another preferred method within the scope of the present invention is a method for improving patient function, the method comprising the step of intracranially administering a neurotoxin to a patient, thereby improving patient function as determined by improvement in one or more of the factors of reduced pain, reduced time spent in bed, increased ambulation, healthier attitude and a more varied lifestyle.

DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that one or more endocrine disorders can be effectively treated by intracranial, in vivo, local administration of an neurotoxin to a human patient. Generally, hormonal excess results in a pathological condition and one aspect of the present invention is directed to methods for treating hormone excess resulting from overproduction of a hypothalamic releasing factor or of a pituitary hormone. The present invention is also based on the discovery that gametogenesis, and hence conception, can be inhibited by intracranial, in vivo, local administration of an neurotoxin to a male or female human patient.

Thus, the present invention reveals that significant and lost lasting relief from a variety of different endocrine disorders can be achieved by intracranial administration of a neurotoxin. Intracranial administration permits the blood brain barrier to be bypassed and delivers much more toxin to the brain than is possible by a systemic route of administration. Furthermore, systemic administration of a neurotoxin, such as a botulinum toxin, is contraindicated due to the severe complications (i.e. botulism) which can result from entry of a botulinum toxin into the general circulation. Additionally, since botulinum toxin does not penetrate the blood brain barrier to any significant extent, systemic administration of a botulinum toxin has no practical application to treat an intracranial target tissue.

According to the present, in vivo local administration of a neurotoxin, such as a botulinum toxin, can be used to treat a variety of conditions which can benefit from inhibition of the hypothalamic-pituitary-gonadal axis such as hypergonadotrophic hypergonadism. Thus, a method according to the present invention can be used to treat hypergonadotrophic hypergonadism by decreasing a hypothalamic or pituitary secretion.

Additionally, a method according to the present can be used to influence the secretion of gonadotropin releasing hormone (GnRH) by locally administering a preparation influencing central cholinergic activity. In brief, the present invention provides methods for treatment of conditions that can benefit from inhibition of the hypothalamic-pituitary-gonadal axis, for prevention gametogenesis (i.e. inhibition of ovulation or of sperm production--hence contraception) and to treat hypergonadotrophic hypergonadism.

Without wishing to be bound by theory it can be hypothesized that a mechanism by which a method according to the present invention achieves a desired result is due to inhibition of a cholinergic influence over an endocrine hypothalamic or pituitary tissue by the disclosed local administration of a neurotoxin. Inhibition of a hypothalamic cholinergic influence results, for example, in a decreased release of hypothalamic GnRH, which in turn causes a reduced anterior pituitary release of LH and FSH. A reduction is circulating LH and FSH release can be an effective means of inhibiting conception, and treating various hypergonadic conditions. Thus, a neurotoxin, such as a botulinum toxin, can inhibit neuronal exocytosis of several different CNS neurotransmitters, in particular acetylcholine. It is known that cholinergic neurons are present in both the hypothalamus and in the pituitary. Thus, target tissues for a method within the scope of the present invention can include neurotoxin induced reversible denervation of intracranial areas, such as the hypothalamus. For example, injection or implantation of a neurotoxin to a cholinergically innervated hypothalamic nuclei (such as the arcuate nucleus) can result in a suppression of GHRH and thus GH secretion due to the action of the toxin upon cholinergic terminals projecting into the hypothalamus, and; (2) attenuation of hypothalamic regulatory hormone output due to the action of the toxin upon hypothalamic somata, both cholinergic and non-cholinergic, thereby producing a chemical and therapeutic hypothalamotomy.

As disclosed, the present invention relates to use of a neurotoxin to modulate the hypothalamic-pituitary-gonadal axis through a direct, local administration of a neurotoxin to the hypothalamus and or to the pituitary. In particular, the present invention relates to local, central administration of a neurotoxin to modulate the hypothalamic-pituitary-gonadal axis by inhibiting the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus.

Suitable neurotoxins for use in the present invention include non-cytotoxic (i.e. no significant neuron or other cell death/necrosis) neurotoxins which can reversibly inhibit one or hypothalamic and/or pituitary endocrine secretions without significant effect, upon other non-hypothalamic or non-pituitary target tissue. Suitable compounds for this purpose are the botulinum toxins.

The present invention encompasses any suitable method for intracranial administration of a neurotoxin to a selected target tissue, including injection of an aqueous solution of a neurotoxin and implantation of a controlled release system, such as a neurotoxin incorporating polymeric implant at the selected target site. Use of a controlled release implant reduces the need for repeat injections. Intracranial implants are known. For example, brachytherapy for malignant gliomas can include stereotatically implanted, temporary, iodine-125 interstitial catheters. Scharfen. C. O., et al., High Activity Iodine-125 Intersitial Implant For Gliomas, Int. J. Radiation Oncology Biol Phys 24(4);583-591:1992. Additionally, permanent, intracranial, low dose 125 I seeded catheter implants have been used to treat brain tumors. Gaspar, et al., Permanent 125 I Implants for Recurrent Malignant Gliomas, Int J Radiation Oncology Biol Phys 43(5);977-982:1999. See also chapter 66, pages 577-580, Bellezza D., et al., Stereotactic Interstitial Brachytherapy, in Gildenberg P. L. et al., Textbook of Stereotactic and Functional Neurosurgery, McGraw-Hill (1998).

Furthermore, local administration of an anti cancer drug to treat malignant gliomas by interstitial chemotherapy using surgically implanted, biodegradable implants is known. For example, intracranial administration of 3-bis(chloro-ethyl)-1-nitrosourea (BCNU) (Carmustine) containing polyanhydride waters, has found therapeutic application. Brem, H. et al., The Safety of Interstitial Chemotherapy with BCNU-Loaded Polymer Followed by Radiation Therapy in the Treatment of Newly Diagnosed Malignant Gliomas: Phase I Trial, J Neuro-Oncology 26:111-123:1995.

A polyanhydride polymer, Gliadel.RTM. (Stolle R & D, Inc., Cincinnati, OH) a copolymer of poly-carboxyphenoxypropane and sebacic acid in a ratio of 20:80 has been used to make implants, intracranially implanted to treat malignant gliomas. Polymer and BCNU can be co-dissolved in methylene chloride and spray-dried into microspheres. The microspheres can then be pressed into discs 1.4 cm in diameter and 1.0 mm thick by compression molding, packaged in aluminum foil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads of gamma irradiation. The polymer permits release of carmustine over a 2-3 week period, although it can take more than a year for the polymer to be largely degraded. Brem, H., et al, Placebo-Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gilomas, Lancet 345;10081012:1995.

An implant can be prepared by mixing a desired amount of a stabilized neurotoxin (such as non-reconstituted BOTOX.RTM.) into a solution of a suitable polymer dissolved in methylene chloride, at room temperature. The solution can then transferred to a Petri dish and the methylene chloride evaporated in a vacuum desiccator. Depending upon the implant size desired and hence the amount of incorporated neurotoxin, a suitable amount of the dried neurotoxin incorporating implant is compressed at about 8000 p.s.i. for 5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implant discs encapsulating the neurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of Interstitial Delivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel From a Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58;672-684:1998. Diffusion of biological activity of a botulinum toxin within a tissue appears to be a function of dose and can be graduated. Jankovic J., et al Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150.

Local, intracranial delivery of a neurotoxin, such as a botulinum toxin, can provide a high, local therapeutic level of the toxin and can significantly prevent the occurrence of any systemic toxicity since many neurotoxins, such as the bolulinum toxins are too large to cross the blood brain barrier. A controlled release polymer capable of long term, local delivery of a neurotoxin to an intracranial site can circumvent the restrictions imposed by systemic toxicity and the blood brain barrer, and permit effective dosing of an intracranial target tissue. Suitable neurotoxin and botulinum toxin implants for use In the present invention, are set forth in co-pending U.S. patent applications Ser. No. 09/587250 entitled "Neurotoxin Implant and Ser. No. 09/624003, entitled "Botulinum Toxin Implant". Such an implant permits direct introduction of a chemotherapeutic agent to a brain target tissue via a controlled release polymer. The implant polymers used are preferably hydrophobic so as to protect the polymer incorporated neurotoxin from water induced decomposition until the toxin is released into the target tissue environment.

Local intracranial administration of a botulinum toxin, according to the present invention, by injection or implant to e.g. the cholinergic hypothalamus presents as a superior alternative to hypothalamotomy in the management of inter alia hypergonadothophism.

A method within the scope of the present invention includes stereotactic placement of a neurotoxin containing implant using the Riechert-Mundinger unit and the Z D (Zamorano-Dujovny) multipurpose localizing unit. A contrast-enhanced computerized tomography (CT) scan, injecting 120 ml of omnipaque, 350 mg iodine/ml, with 2 mm slice thickness can allow three dimensional multiplanar treatment planning (STP, Fischer, Freiburg, Germany). This equipment permits planning on the basis of magnetic resonance imaging studies, merging the CT and MRI target information for clear target confirmation.

The LekseII stereotactic system (Downs Surgical, Inc., Decatur, Ga.) modified for use with a GE CT scanner (General Electric Company, Milwaukee, Wis.) as well as the Brown-Roberts-Wells (B R W) stereotactic system (Radionics, Burlington, Md.) have been used for this purpose. Thus, on the morning of the implant, the annular base ring of the B R W stereotactic frame can be attached to the patient's skull. Serial CT sections can be obtained at 3 mm intervals though the (target tissue) region with a graphite rod localizer frame clamped to the base plate. A computerized treatment planning program can be run on a VAX 11/780 computer (Digital Equipment Corporation, Maynard, Mass.) using CT coordinates of the graphite rod images to map between CT space and B R W space.

Preferably, a neurotoxin used to practice a method within the scope of the present invention is a botulinum toxin, such as one of the serotype A, B, C, D, E, F or G botulinum toxins. Preferably, the botulinum toxin used is botulinum toxin type A, because of its high potency in humans, ready availability, and known use for the treatment of skeletal and smooth muscle disorders when locally administered by intramuscular injection. Botulinum toxin type B is a less preferred neurotoxin to use in the practice of the disclosed methods because type B is known to have a significantly lower potency and efficacy as compared, to type A, is not readily available, and has a limited history of clinical use in humans. Furthermore, the higher protein load with regard to type B can cause immunogenic reaction to occur with development of antibodies to the type B neurotoxin.

The amount of a neurotoxin selected for intracranial administration to a target tissue according to the present disclosed invention can be varied based upon criteria such as the endocrine disorder being treated, its severity, the extent of brain tissue involvement or to be treated, solubility characteristics of the neurotoxin toxin chosen as well as the age, sex, weight and health of the patient. For example, the extent of the area of brain tissue influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the hypothalamic or pituitary secretion suppressant effect is, for most dose ranges, believed to be proportional to the concentration of neurotoxin injected. Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14th edition, published by McGraw Hill).

I have found that a neurotoxin, such as a botulinum toxin, can be intracranially administered according to the present disclosed methods in amounts of between about 10-2 units to about 500 units. A dose of about 10-2 units can result in a gonadotrophin suppressant effect if delivered a small nuclei. Intracranial administration of less than about 102 units does not result in a significant or lasting therapeutic result. An intracranial dose of more than 500 units of a neurotoxin, such as a botulinum toxin, poses a significant risk of denervation of sensory or desirable motor functions of neurons adjacent to the target

Less than about 10-2 U/kg can result in a relatively minor, though still observable, gonadotrophin suppressant effect. A more preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a gonadotrophin suppressant effect in the patient treated is from about 10-1 U/kg to about 50 units. Less than about 10-1 U/kg can result in the desired therapeutic effect being of less than the optimal or longest possible duration. A most preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a desired gonadotrophin suppressant effect in the patient treated is from about 0.1 units to about 10 units. Intracranial administration of a botulinum toxin, such as botulinum toxin type A, in this preferred range can provide dramatic therapeutic success.

The present invention includes within its scope the use of any neurotoxin which has a long duration gonadotrophin suppressant effect when locally applied intracranially to the patient. For example, neurotoxins made by any of the species of the toxin producing Clostridium bacteria, such as Clostridium botulinum, Clostridium butydricum, and Clostridium beratti can be used or adapted for use in the methods of the present invention. Additionally, all of the botulinum serotypes A, B, C1, D, E, F and G can be advantageously used in the practice of the present invention, although type A is the most preferred and type B the least preferred serotype, as explained above. Practice of the present invention can provide a gonadotrophin suppressant effect, per injection, for 3 months or longer in humans.

SignifIcantly, a method within the scope of the present invention can provide improved patient function. "Improved patient function" can be defined as an improvement measured by factors such as a reduced pain, reduced time spent in bed, increased ambulation, healthier attitude, more varied lifestyle and/or healing permitted by normal muscle tone. Improved patient function Is synonymous with an improved quality of life (QOL). QOL can be assesses using, for example, the known SF-12 or SF-36 health survey scoring procedures. SF-36 assesses a patient's physical and mental health in the eight domains of physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health perceptions. Scores obtained can be compared to published values available for various general and patient populations.

As set forth above, I have discovered that a surprisingly effective and long lasting treatment of an endocrine disorder can be achieved by intracranial administration of a neurotoxin to an afflicted patient. In its most preferred embodiment, the present invention is practiced by intracranial injection or implantation of botulinum toxin type A.

The present invention does include within its scope: (a) neurotoxin obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying and/or reconstitution and; (b) modified or recombinant neurotoxin, that is neurotoxin that has had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made.

Botulinum toxins for use according to the present invention can be stored in lyophilized, vacuum dried form in containers under vacuum pressure or as stable liquids. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized material can be reconstituted with saline or water.

Claim 1 of 17 Claims

I claim:

1. A method for treating an endocrine condition, the method comprising the step of intracranial administration of a therapeutically effective amount of a botulinum toxin selected from the group consisting of botulinum toxin types A, B, C1, D, E, and G to the hypothalamus or pituitary of a patient, thereby treating a symptom of an endocrine condition by reducing a secretion of a hypothalamic or pituitary hormone or releasing hormone, wherein the endocrine condition is selected form the group consisting of gametogenesis, menstruation, acromegaly, gigantism, Cushing's disease, hypergonadism and hyperthyroidism.


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