Controlled administration of chemodenervating pharmaceuticals

• US 5,183,462 A
• Filed: 08/21/1990
• Issued: 02/02/1993
• Est. Priority Date: 08/21/1990
• Status: Expired due to Fees

• Current Assignee: Revance Therapeutics, Inc.
• Original Assignee: Associated Synapse Biologics
• Inventors: Borodic, Gary E.
• Primary Examiner(s): Millin, V.
• Assistant Examiner(s): Passaniti, Sebastiano
• Application Number:
  US07/570,395
• Time in Patent Office: 896 Days
• Field of Search: 604/49-53, 604/28, 128/749, 128/898, 128/632, 128/635, 128/DIG. 13, 514/903, 206/570
• US Class Current: 604/506
• CPC Class Codes: A61K 38/4893 Botulinum neurotoxin (3.4.24.69)
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61K 8/99 from microorganisms other than algae or fungi, e.g. protozoa or bacteria
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to a method for controlled administration of chemodernervating agents such as botulinum toxin-derived pharmaceutical, useful in attenuating neural stimulation and spasmotic activity of muscle. The method involves administration of novel dosage forms based upon the standardization of denervating pharmaceuticals. The invention also relates to novel methods of administering chemodernervating agents in a controlled and reproducible manner so as to confine their effects to a given region of muscle mass while minimizing paresis in adjacent muscle tissue.

Claims

1. A method of standardizing dosages of a chemodenervating preparation by relating extent of denervation in a muscle or muscle group of an experimental animal to a unit quantity of said preparation comprising the steps of injecting a unit quantity of said preparation into said muscle or muscle group of an experimental animal, permitting said preparation to diffuse within said muscle or muscle group about the site of said injection and to physiologically inhibit acetylcholine release, and determining the spatial extent of inhibition of acetylcholine release about the site of injection within said muscle or group per said unit quantity of said preparation, thereby providing a reliable indicator to a clinician of a volume of said muscle or muscle group which is denervated by a quantity of said preparation.

2. The method of claim 1 comprising determining the local concentration of acetylcholinesterase in regions of said muscle spaced apart from said site of injection.

3. The method of claim 2 wherein the local concentration is determined by histochemical estimation of acetylcholinesterase enzyme activity.

4. The method of claim 1 comprising determining the extent of inhibition of muscle stimulation in regions of said muscle spaced apart from said site of injection by electrophysiologic testing.

5. The method of claim 1 comprising determining the density of acetylcholine receptors or acetylcholinesterase in regions of said muscle spaced apart from said site of injection.

6. The method of claim 5 wherein the density of said acetylcholine receptors or acetylcholinesterase is determined by binding labeled antibodies to said receptors or acetylcholinesterase.

7. The method of claim 1 wherein said preparation is a botulinum toxin-derived preparation.

8. A method of selectively chemically partially denervating a predetermined volume of a muscle or muscle group without inducing significant paresis in muscle tissue adjacent said predetermined volume, the method comprising the steps of:

providing a chemodenervating pharmaceutical characterized in that a unit quantity of said pharmaceutical has been determined to denervate said predetermined volume of a muscle or muscle group;

determining a dose of said pharmaceutical required to denervate the predetermined volume of muscle without inducing significant paresis in muscle tissue adjacent said predetermined volume;

injecting said dose directly into a point within said predetermined volume; and

permitting said dose to diffuse throughout said predetermined volume to induce partial denervation thereof.

9. The method of claim 8 comprising providing plural doses of said pharmaceutical and injecting individual ones of said doses into sites spaced apart within said predetermined volume of muscle, the spatial relationship of the sites being sufficient to at least partially denervate the entirety of said predetermined volume.

10. The method of claim 8 wherein said volume of muscle co a single muscle, the method comprising providing said dose of said pharmaceutical and injecting said dose into the innervating zone of said muscle, and permitting said dose to diffuse through said innervating zone to induce partial denervation of the entirety of said muscle.

11. The method according to claim 8 wherein spasm or involuntary contraction in said muscle or muscle group, of a patient induced by pathologic neural stimulation caused by cerebrospinal injury or stroke is decreased by partially denervating said predetermined volume of said muscle or muscle group in spasm or involuntary contraction.

12. A method of decreasing spasm or involuntary contraction in a muscle or group of muscles of a patient induced by pathologic neural stimulation caused by cerebral palsy or multiple sclerosis, the method comprising:

providing a chemodenervating pharmaceutical characterized in that a unit quantity of said pharmaceutical has been determined to denervate a predetermined volume of said muscle or muscle group;

determining a dose of said pharmaceutical required to denervate the predetermined volume of muscle without inducing significant paresis in muscle tissue adjacent said predetermined volume;

injecting directly into a point of said muscle or muscle group of said patient suffering from cerebral palsy or multiple sclerosis said dose of said chemodenervating pharmaceutical to decrease the spasm and involuntary contraction in said muscle or muscle group.

15. The method of claim 12, 13 or 14 wherein said denervating pharmaceutical comprises a neurotoxin derived from Clostridium botulinum.

13. A method of decreasing tremor, rigidity or spasticity in a muscle or group of muscles of a patient afflicted with Parkinson'"'"'s disease, the method comprising:

providing a chemodenervating pharmaceutical characterized in that a unit quantity of said pharmaceutical has been determined to denervate a predetermined volume of said muscle or muscle group;

determining a dose of said pharmaceutical required to denervate the predetermined volume of muscle without inducing significant paresis in muscle tissue adjacent said predetermined volume;

injecting directly into said muscle or muscle group of said patient afflicted with Parkinson'"'"'s disease said dose of said pharmaceutical to decrease said rigidity or spasticity in said muscle or muscle group.

14. A method of cosmetically decreasing facial wrinkling in a patient induced by contraction of an underlying facial muscle or group of muscles, the method comprising:

providing a chemodenervating pharmaceutical characterized in that a unit quantity of said pharmaceutical has been determined to denervate a predetermined volume of said muscle or muscle group;

determining a dose of said pharmaceutical required to denervate the predetermined volume of muscle without inducing significant paresis in muscle tissue adjacent said predetermined volume;

injecting directly into said facial muscle or muscle group of said patient having said wrinkling said dose of said pharmaceutical to denervate said muscle thereby temporarily reducing the wrinkling caused by contraction of said muscle or muscle group.