Method for treating premature ejaculation with a neurotoxin
09764010 · 2017-09-19
Assignee
Inventors
Cpc classification
A61P15/00
HUMAN NECESSITIES
International classification
Abstract
Methods for treating premature ejaculation and prolongation of climax time in a patient in need thereof by local administration of a Clostridial neurotoxin, such as a botulinum toxin, are provided.
Claims
1. A method for treating premature ejaculation in a patient, the method comprising the step of locally administering a therapeutically effective amount of botulinum toxin to a pudendal nerve near or at the base of the penis of the patient, thereby treating the premature ejaculation of the patient.
2. The method of claim 1, wherein between about 5 and about 200 units of botulinum toxin is administered.
3. The method of claim 1, wherein the botulinum toxin is administered by injection to the dorsal base of the penis.
4. The method of claim 3, wherein the botulinum toxin is administered by at least two injections performed bilaterally on both sides of the midline of the dorsal base of the penis.
5. The method of claim 4, wherein the botulinum toxin is administered into the area between the Bucks fascia and the Tunica albuginea, in proximity to the pudendal nerve.
6. The method of claim 5, further comprising administering the botulinum toxin to the bulbospongiosus muscle.
7. The method of claim 1, wherein the botulinum toxin is administered topically.
8. The method of claim 1, further comprising administering the botulinum toxin to the bulbospongiosus muscle.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
(3) The present invention encompasses a method for treating premature ejaculation by local administration of a Clostridial toxin or its variants to a mammal, such as a human patient. Preferably, the Clostridial toxin is a botulinum toxin. In certain embodiments the botulinum toxin is a botulinum toxin type A. The botulinum toxin can be administered in an amount between about 1 unit and about 10,000 units and premature ejaculation and/or prolongation of climax time can be alleviated for between about 2 weeks and about 6 months. In particular examples, premature ejaculation and/or prolongation of climax time can be alleviated from about 2 months to about 6 months, or from about 4 to about 6 months, for example. In one aspect, the local administration step is carried out by direct administration of the Clostridial toxin, such as a botulinum neurotoxin, to at least one location of a penis of the patient.
(4) In another embodiment, a method for treating premature ejaculation in a patient in need thereof is provided, where the method comprises a step of locally administering, by injection, a botulinum neurotoxin to the area near or at the base of the penis, thereby treating premature ejaculation in the patient. In particular embodiments, the botulinum neurotoxin is injected into at least two penile locations, and in some examples at least three penile locations. In certain embodiments, local administration of botulinum neurotoxin in the area near or at the dorsal base of the penis is into the area between the Bucks fascia and the Tunica albuginea, in proximity to the Pudendal nerve. Exemplary amounts being from about 1 to about 2500 units of a botulinum toxin type A, or any amount therebetween. When utilizing a botulinum toxin type B for example, the administered amount can be from between about 1 unit and about 25,000 units, or from about 100 units to about 20,000 units or from about 500 units to about 15,000 units or any amount therebetween.
(5) In particular embodiments, additional administration of botulinum neurotoxin to the penis of the patient can be performed, for example from at least about 2 months to about 3 months or more after an initial administration of botulinum neurotoxin to the penis.
(6) In particular embodiments, local administration of the botulinum neurotoxin type A is from about 1 unit to about 500 units, per injection site, per patient visit. In certain embodiments the local administration of botulinum toxin type A for treating premature ejaculation is at a dose of about 1 unit, about 2 units, about 3 units, about 4 units, about 5 units, about 6.25 units, about 10 units, about 12.5 units, about 15 units, about 20 units, about 25 units, about 30 units, about 35 units, about 37.5 units, about 40 units, about 50 units, about 55 units, about 60 units, about 65 units, about 70 units, about 75 units, about 80 units, about 85 units, about 90 units, about 95 units, about 100 units, about 105 units, about 110 units, about 115 units, about 120 units, about 125 units, about 130 units, about 135 units, about 140 units, about 145 units, about 150 units, about 155 units, about 160 units, about 165 units, about 170 units, about 175 units, about 180 units, about 185 units, about 190 units, about 195 units, or about 200 units, per injection site, per patient visit.
(7) In particular embodiments, local administration of a botulinum neurotoxin can be to two bilateral locations on the base of the penis. In other embodiments, additional injection locations include the bulbospongiosus muscle.
(8) Additionally, a method for prolongation of climax time in a patient in need thereof is provided wherein the method comprises the step of locally administering a botulinum neurotoxin to the base of the penis to thereby prolong the climax time in the patient. Administration of botulinum neurotoxin can be via transdermal, intramuscular, subcutaneous, subdermal, intradermal or implant administration, and can be to the dorsal base of the penis. In particular embodiments, the botulinum neurotoxin is administered by injection into the base of the penis, and the botulinum neurotoxin is botulinum neurotoxin type A or type B. In further embodiments a method for prolongation of climax time in a patient in need thereof is provided wherein the method comprises the step of locally administering a botulinum neurotoxin to the dorsal base of the penis to target the pudendal nerve, thereby prolonging the climax time in the patient.
(9) In certain embodiments an appropriate needle for botulinum toxin injection include needles of 30-guage or smaller, preferably from about 23-gauge to about 25-gauge, and the area is preferably cleaned, such as with alcohol, before injection. Local anesthetic cream, general anesthesia, sedation or any known be useful anesthetic may be utilized, and may be necessary, depending upon the particular patient (some patients being more sensitive than others) undergoing treatment in accordance with the present methods. In particular examples, topical use of an anesthetic cream, such as, for example benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, and tetracaine can be applied before administration of the botulinum toxin via a needle.
(10) In some instances, the dosage of botulinum neurotoxin administered can be increased until achieving the desired effect (e.g. until the patient is satisfied with the resultant delay in ejaculation). In a particular embodiment, a first dosage can be from about 10 units to about 75 units of a botulinum toxin, or from about 25 units to about 50 units of a botulinum toxin, such as BOTOX®. If unsatisfactory results are observed, treatment dosage can be increased, as determined by the medical practitioner's evaluation of the particular case at hand, the dosage, for example, being increased up to about 100 or about 200 units of a botulinum toxin. In such instances, the time between administration of increasing dosages of botulinum toxin can be about 3 weeks, preferably about 1 month and most preferably about 2 months.
(11) The age range of patients upon which the methods herein disclosed can be practiced can be from about 18 years old to about 75 years old, more particularly, from about 18 years old to about 40 years old, and even more particularly, from about 18 years old to about 30 years old. In particular instances, the patient has tried various previous treatments that have not been found to satisfactorily treat the patient's premature ejaculation.
(12) In some instances premature ejaculation can be experienced even after the beginning of sexual intercourse, that this, even if a patient is able to penetrate their partner (i.e. not ejaculate prior to penetration), ejaculation prematurely follows. In such instances, it is the time period between penetration and ejaculation that considered to be too short, and accordingly prolongation of climax time, here increasing the time from which sexual intercourse begins to the time of ejaculation, is desired. In particular non-limiting examples, a patient may be considered to suffer from premature ejaculation if ejaculation is achieved after from about 10 seconds to about 15 minutes after penetration, from about 15 seconds to about 10 minutes after penetration or from about 30 seconds to about 5 minutes after penetration. In particular cases, a patient may be considered to suffer from premature ejaculation if ejaculation is achieved after from about 10 seconds to about 3 minutes after penetration, from about 25 seconds to about 2 minutes after penetration or from about 30 seconds to about 1 minute after penetration.
(13) Patients that can be treated by the methods herein disclosed may have previously partaken in regimens for treating their premature ejaculation or for prolongation of their climax time. Exemplary regiments can include taking a selective serotonin reuptake inhibitor, such as fluoxetine or paroxetine, for example. Other approaches that may have been tried include application of topical anesthetics, such as lidocaine 5% cream, applied to the penis before intercourse. Such approaches can, if desired, be combined with the methods herein disclosed in order to treat premature ejaculation or for prolongation of climax time.
(14) In particular embodiments the botulinum neurotoxin is administered on an as-needed basis. Dosing will be determined for, and be particular to, the patient/particular presentation of premature ejaculation, with non-limiting, exemplary amounts provided herein. For example, duration of effect after botulinum administration can be up to about 4 months after administration. In particular instances, the duration of effect after botulinum administration can be from about 2 days to about 3 months after botulinum administration. Shorter duration of effects can be associated with a botulinum toxin having a short acting profile/duration of effect, such as botulinum toxin type E, relative to another botulinum toxin, such as a botulinum toxin type A, for example.
(15) The present invention includes within its scope: (a) a botulinum neurotoxin complex as well as a pure botulinum neurotoxin obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying and/or reconstitution and; (b) modified or recombinant botulinum neurotoxin, that is botulinum 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 botulinum neurotoxins so made, and includes botulinum neurotoxins with one or more attached non-native targeting moieties for a cell surface receptor present on a cell.
(16) Preferably, because of its clinical history to successfully treat a number of indications, a method within the scope of the present invention includes local administration of a botulinum type A or botulinum toxin type B, although botulinum toxin type B is used with a larger protein load, as compared to type A toxin. A botulinum toxin type A used in a method within the scope of the present invention can be a complex of toxin and non-toxin proteins, which together comprise a total molecular weight of up to about 900 kDa. Dosage ranges and amounts, like any pharmaceutical, are based upon size, age and health of the patient, as well as upon the particular commercial preparation of the botulinum toxin used. As known in the art, therapeutic use of botulinum toxins is tailored to the particular patient that is presented for treatment, e.g. to treat premature ejaculation. A botulinum toxin type B used in a method within the scope of the present invention can be a pure toxin or complex of toxin and non-toxin proteins, which is used at a dose of between about 50 and about 20,000 units. Other botulinum toxin serotypes may be used in proportion to the dosages and concentrations exemplified herein, according to their respective levels of biological activity. For example, most units listed in the instant disclosure are of BOTOX®, but different serotypes or strains of a botulinum toxin may be used, and different amounts may be administered. For example, about 3-4 times of DYSPORT® (a botulinum toxin type A complex available from Ipsen Inc.) than an amount of BOTOX® may be utilized; about 40-50 times of NEUROBLOC®/MYOBLOC® (a botulinum toxin type B available from Solstice Neurosciences) than an amount of BOTOX® may be utilized; and about equivalent amounts, in units, of XEOMIN® (pure botulinum toxin type A, by Merz Pharma) relative to BOTOX® units can be utilized, to achieve a desired therapeutic effect, respectively. The present invention also encompasses methods for concurrent or serial administration of a mixture of two or more of the above neurotoxins to effectively treat a patient with premature ejaculation.
Definitions
(17) As used herein, the words or terms set forth below have the following definitions:
(18) “About” or “approximately” as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, (i.e., the limitations of the measurement system). For example, “about” can mean within 1 or more than 1 standard deviations, per practice in the art. Where particular values are described in the application and claims, unless otherwise stated, the term “about” means within an acceptable error range for the particular value.
(19) “Active pharmaceutical ingredient” (API) means an ingredient that exerts an effect upon or after administration to a subject or patient. API's can include, for example, botulinum toxins, and the like.
(20) “Administration”, or “to administer” means the step of giving (i.e. administering) a pharmaceutical composition to a subject, or alternatively a subject receiving a pharmaceutical composition. The pharmaceutical compositions disclosed herein can be locally administered by various methods. For example, intramuscular, intradermal, subcutaneous administration, intrathecal administration, intraperitoneal administration, topical (transdermal), instillation, and implantation (for example, of a slow-release device such as polymeric implant or miniosmotic pump) can all be appropriate routes of administration.
(21) “Alleviating” means a reduction in the occurrence of a pain, of a headache, or of any symptom or cause of a condition or disorder. Thus, alleviating includes some reduction, significant reduction, near total reduction, and total reduction.
(22) “Biological activity” describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient but can be modified by the other constituents. Biological activity can be assessed as potency or as toxicity by an in vivo LD.sub.50 or ED.sub.50 assay, or through an in vitro assay such as, for example, cell-based potency assays as described in U.S. 20100203559 and U.S. 20100233802.
(23) “Botulinum toxin” means a neurotoxin produced by Clostridium botulinum, as well as a botulinum toxin (or the light chain or the heavy chain thereof) made recombinantly by a non-Clostridial species. The phrase “botulinum toxin”, as used herein, encompasses the botulinum toxin serotypes A, B, C, D, E, F and G, and their subtypes and any other types of subtypes thereof, or any re-engineered proteins, analogs, derivatives, homologs, parts, sub-parts, variants, or versions, in each case, of any of the foregoing. “Botulinum toxin”, as used herein, also encompasses a “modified botulinum toxin”. Further “botulinum toxin” as used herein also encompasses a botulinum toxin complex, (for example, the 300, 600 and 900 kDa complexes), as well as the neurotoxic component of the botulinum toxin (150 kDa) that is unassociated with the complex proteins.
(24) “Climax baseline time” is the pre-treatment climax time of a patient, that is, the time or average time that it takes for a patient to climax after becoming sexually aroused.
(25) “Climax time” or “Ejaculation time” is the time between the start of sexual intercourse (i.e. penetration of the partner) and ejaculation (i.e. when climax is achieved).
(26) “Clostridial neurotoxin” means a neurotoxin produced from, or native to, a Clostridial bacterium, such as Clostridium botulinum, Clostridium butyricum or Clostridium beratti, as well as a Clostridial neurotoxin made recombinantly by a non-Clostridial species.
(27) “Deformity” means a cosmetic, physical or functional irregularity, defect, abnormality, imperfection, malformation, depression, or distortion.
(28) “Entirely free (i.e. “consisting of” terminology) means that within the detection range of the instrument or process being used, the substance cannot be detected or its presence cannot be confirmed.
(29) “Essentially free” (or “consisting essentially of”) means that only trace amounts of the substance can be detected.
(30) “Light chain” means the light chain of a clostridial neurotoxin. It has a molecular weight of about 50 kDa, and can be referred to as the L chain, L, or as the proteolytic domain (amino acid sequence) of a botulinum neurotoxin.
(31) “Heavy chain” means the heavy chain of a botulinum neurotoxin. It has a molecular weight of about 100 kDa and can be referred to as the H chain, or as H.
(32) H.sub.C means a fragment (about 50 kDa) derived from the H chain of a botulinum neurotoxin which is approximately equivalent to the carboxyl end segment of the H chain, or the portion corresponding to that fragment in the intact H chain. It is believed to be immunogenic and to contain the portion of the natural or wild type botulinum neurotoxin involved in high affinity, presynaptic binding to motor neurons.
(33) H.sub.N means a fragment (about 50 kDa) derived from the H chain of a botulinum neurotoxin which is approximately equivalent to the amino end segment of the H chain, or the portion corresponding to that fragment in the intact in the H chain. It is believed to contain the portion of the natural or wild type botulinum neurotoxin involved in the translocation of the L chain across an intracellular endosomal membrane.
(34) LH.sub.N or L-H.sub.N means a fragment derived from a clostridial neurotoxin that contains the L chain, or a functional fragment thereof coupled to the H.sub.N domain It can be obtained from the intact clostridial neurotoxin by proteolysis, so as to remove or to modify the H.sub.C domain.
(35) “Implant” means a controlled release (e.g., pulsatile or continuous) composition or drug delivery system. The implant can be, for example, injected, inserted or implanted into a human body.
(36) “Local administration” means direct administration of a pharmaceutical at or to the vicinity of a site on or within an animal body, at which site a biological effect of the pharmaceutical is desired, such as via, for example, intramuscular injection, intra-dermal injection, subdermal injection, subcutaneous injection, placement of an implant for administration of the neurotoxin, or topical administration. Local administration excludes systemic routes of administration, such as intravenous or oral administration. Topical administration is a type of local administration in which a pharmaceutical agent is applied to a patient's skin.
(37) “Modified botulinum toxin” means a botulinum toxin that has had at least one of its amino acids deleted, modified, or replaced, as compared to a native botulinum toxin. Additionally, the modified botulinum toxin can be a recombinantly produced neurotoxin, or a derivative or fragment of a recombinantly made neurotoxin. A modified botulinum toxin retains at least one biological activity of the native botulinum toxin, such as, the ability to bind to a botulinum toxin receptor, or the ability to inhibit neurotransmitter release from a neuron. One example of a modified botulinum toxin is a botulinum toxin that has a light chain from one botulinum toxin serotype (such as serotype A), and a heavy chain from a different botulinum toxin serotype (such as serotype B). Another example of a modified botulinum toxin is a botulinum toxin coupled to a neurotransmitter, such as substance P.
(38) “Mutation” means a structural modification of a naturally occurring protein or nucleic acid sequence. For example, in the case of nucleic acid mutations, a mutation can be a deletion, addition or substitution of one or more nucleotides in the DNA sequence. In the case of a protein sequence mutation, the mutation can be a deletion, addition or substitution of one or more amino acids in a protein sequence. For example, a specific amino acid comprising a protein sequence can be substituted for another amino acid, for example, an amino acid selected from a group which includes the amino acids alanine, aspargine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine or any other natural or non-naturally occurring amino acid or chemically modified amino acids. Mutations to a protein sequence can be the result of mutations to DNA sequences that when transcribed, and the resulting mRNA translated, produce the mutated protein sequence. Mutations to a protein sequence can also be created by fusing a peptide sequence containing the desired mutation to a desired protein sequence.
(39) “Neurotoxin” includes Clostridial neurotoxins both as pure toxin and complexed with one to more non-toxin, toxin associated proteins, whether made by the native Clostridial bacterium or by recombinant means in a non-Clostridial species. “Botulinum neurotoxin” means non-complexed botulinum neurotoxin (i.e. pure botulinum neurotoxin molecule having a molecular weight of about 150 kDa) or as a complex (i.e. having a molecular weight of about 300 to about 900 kDa weight complex comprising a neurotoxin molecule and one or more associated non-toxic molecules), and excludes botulinum toxins which are not neurotoxins such as the cytotoxic botulinum toxins C2 and C3, but can include recombinantly made, hybrid, modified, and chimeric botulinum toxins.
(40) “Patient” means a human subject receiving medical care from a physician.
(41) “Peripherally administering” or “peripheral administration” means subdermal, intradermal, transdermal, or subcutaneous administration, but excludes intramuscular administration. “Peripheral” means in a subdermal location, and excludes visceral sites.
(42) “Pharmaceutical composition” means a composition comprising an active pharmaceutical ingredient, such as, for example, a botulinum toxin, and at least one additional ingredient, such as, for example, a stabilizer or excipient or the like. A pharmaceutical composition is therefore a formulation which is suitable for diagnostic or therapeutic administration to a subject, such as a human patient. The pharmaceutical composition can be, for example, in a lyophilized or vacuum dried condition, a solution formed after reconstitution of the lyophilized or vacuum dried pharmaceutical composition, or as a solution or solid which does not require reconstitution.
(43) “Prolongation of climax time” means an increase in time (increase in climax baseline time) from which a patient becomes sexually aroused to the time of sexual climax (i.e. orgasm). In one aspect, “treating premature ejaculation” means increasing the time between the beginning of sexual arousal of a patient and ejaculation by the patient; and in particular instances, it can mean increasing the time from which sexual intercourse begins to the time of ejaculation.
(44) “Therapeutic formulation” means a formulation can be used to treat and thereby alleviate a disorder or a disease, such as, for example, premature ejaculation.
(45) “Therapeutically effective amount,” as used herein, means an amount of a Clostridial neurotoxin, for example a botulinum toxin type A, B, C, D, E, F and G, that ameliorates, or eliminates one or more symptoms of a particular disease or condition such as premature ejaculation.
(46) “Topical administration” excludes systemic administration of the neurotoxin. In other words, and unlike conventional therapeutic transdermal methods, topical administration of botulinum toxin does not result in significant amounts, such as the majority of, the neurotoxin passing into the circulatory system of the patient.
(47) “Treating” means to alleviate (or to eliminate) at least one symptom, either temporarily or permanently. Here, this includes increasing the time (i.e. prolongation of climax time) it takes a patient to reach climax after sexual arousal. In a particular example, climax time is the time between the start of intercourse and the time at which climax is achieved.
(48) “Variant” means a clostridial neurotoxin, such as wild-type botulinum toxin serotype A, B, C, D, E, F or G, that has been modified by the replacement, modification, addition or deletion of at least one amino acid relative to wild-type botulinum toxin, which is recognized by a target cell, internalized by the target cell, and catalytically cleaves a SNARE (SNAP (Soluble NSF Attachment Protein) Receptor) protein in the target cell.
(49) An example of a variant neurotoxin component can comprise a variant light chain of a botulinum toxin having one or more amino acids substituted, modified, deleted and/or added. This variant light chain may have the same or better ability to prevent exocytosis, for example, the release of neurotransmitter vesicles. Additionally, the biological effect of a variant may be decreased compared to the parent chemical entity. For example, a variant light chain of a botulinum toxin type A having an amino acid sequence removed may have a shorter biological persistence than that of the parent (or native) botulinum toxin type A light chain.
(50) “Vehicle” or “reconstitution vehicle” means a liquid composition that can be used to reconstitute a solid botulinum formulation into a liquid botulinum pharmaceutical composition.
(51) “Wild type neuronal binding moiety” means that portion of a neurotoxin which is native to the neurotoxin and which exhibits a specific binding affinity for a receptor on a neuron. Thus, wild type or native neuronal binding moiety excludes a binding moiety with is not native to the neurotoxin.
(52) Methods of Treatment
(53) In at least one embodiment, a method of treating premature ejaculation is provided wherein a therapeutic amount of Clostridial neurotoxin such as a botulinum toxin is injected locally: (i) proximally at the dorsal base of the penis (similar to penile nerve block approach); and (ii) additional pelvi-perianal administration into the bulbospongiosus muscle.
(54) In at least one embodiment, a method of treating premature ejaculation is provided wherein injection of a therapeutic amount of Clostridial neurotoxin such as a botulinum toxin is used to block the nerve pathways through the pudendal nerve. In this method, reduced sensory signaling can reduce the trigger of the ejaculatory reflex, and as ejaculation is a spinal cord reflex, inhibiting the stereotyped rhythmic contractions of these muscles with the injection of a Clostridial neurotoxin such as a botulinum toxin, can have a beneficial effect in treating premature ejaculation.
(55) The penis is innervated by the pudendal nerve and cavernous nerves. The pudendal nerve eventually divides into the right and left dorsal nerves of the penis that pass under the pubis symphysis to travel just below the Buck fascia close to the arteries. The pudendal nerves supply somatic motor and sensory innervation to the penis. The cavernous nerves are a combination of parasympathetic and visceral afferent fibers and provide the nerve supply to the erectile tissue. The cavernous nerves run in the crus and corpora of the penis, primarily dorsomedial to the deep penile arteries.
(56) In at least one embodiment a method of treating premature ejaculation by local administration of a botulinum toxin is provided wherein the right and left dorsal penile nerves are blocked proximally to the base of the penis.
(57) In exemplary embodiments, the area that is to receive the botulinum neurotoxin administration is first cleaned utilizing alcohol, such as by utilizing an alcohol wipe, for example. Local anesthetic (as disclosed herein) is then applied to the cleaned area. The anesthetic can be applied topically with local sterile single use local anesthetic (LA) gel or cream (eg, lidocaine gel, cream) and, when ready the injection sites can be sterilized.
(58) An appropriate sized needle (e.g. 22-25 gauge) should be used for injection into the penis.
(59) In at least one embodiment a method of treating premature ejaculation by local administration of a botulinum toxin is provided wherein the botulinum toxin is injected bilaterally through the fascia into the pear shaped spaces on each side of the suspensory ligament. This avoids mid-line injection and therefore potential damage to the dorsal vessels and provides increased chance of diffusion into the nerves to block them. The membranous layer of superficial fascia and the suspensory ligament suspended from the symphysis pubis of the penis, fuses with the deep penile (Buck's) fascia (under which pass the dorsal nerves, arteries and veins, and the penile muscle fibers part of Tunica Albuginea are located). Injection of botulinum toxin is made bilaterally on either side of the midline, avoiding injecting into the superficial dorsal penile vein (see
(60) In at least one embodiment a method of treating premature ejaculation by local administration of a botulinum toxin is provided wherein the botulinum toxin is injected at sites at the perineum and the base of the penis into the bulbospongiosus muscles. Before injection, the scrotum is lifted up to provide an opportunity to identify the base of the penis in the area above the anus and the transverse line across in front of the ischial tuberosities at the sides. The injection is made close to the scrotal base to avoid the anal sphincter muscle. The injection sites can first be aneasthesized topically with local sterile single use local anesthetic (LA) gel or cream (eg, lidocaine gel or cream) applied gently topically and, when ready the injection sites can be sterilized. An appropriate sized needle (e.g. 22-25 gauge) can be used for injection into the penis. Injection is made bilaterally on either side of the midline of the penile basis. The site of insertion of the needle is shown passing through the membranous layer of the deep fascia which covers the nerves and muscles of the perineum (pudendus nerve, ischiocavernous and bulbospongiosus muscles) (see blue lines in
(61) In certain embodiments the patient is observed for at least 60 minutes post-injection. Prior to leaving the site, patients can be checked to see if they experience any adverse events post-treatment.
(62) In certain embodiments, post-procedurally, the patient is instructed not to engage in sexual activity for the following 48 hours, and if edema and/or inflammation is observed, a cold compress or ice pack may be applied. Typically, patients observe effects (e.g. delaying of previously premature ejaculation) within about 48 to about 72 hours, with full results (maximum delay) usually observed after about 3 weeks. The following are non-limiting examples where patient's suffering from premature ejaculation are treated.
EXAMPLES
(63) The following examples illustrate embodiments and aspects of the present invention and are not intended to limit the scope of the present invention.
Example 1
(64) Treatment of premature ejaculation in three cohorts with escalating doses of either a total dose of 25 U or a total dose of 50 U of botulinum toxin type A (BOTOX).
(65) The dilution for the first 25 U total dose cohort is a vial of BOTOX 100 U diluted in 4 mL with 0.9% non-preserved sterile saline i.e. with a final diluted concentration of 25 U/mL. (a) For the 25 U total dose cohort, the patient with the first injection regimen (1) will be injected with 0.5 mL of the diluted BOTOX on each side of the midline into the dorsal base of the penis (i.e. 12.5 U per injection site) and a total injection volume of 1 mL (total dose of 25 U divided in 2 injection sites); (b) For the 25 U total dose cohort the patients with the second injection regimen (2) will be injected both according to regimen (1) but only with 0.25 mL of the diluted BOTOX on each side into the proximal dorsal base of the penis (i.e. 6.25 U per injection site), as well as 0.25 mL of the diluted BOTOX on each side of the midline into the bulbuspongiosus muscles of the perineum (i.e. 6.25 U per injection site) and a total injection volume of 1 mL (total dose of 25 U divided in 4 injection sites).
(66) The dilution for the 50 U dose cohort is a vial of 100 U diluted in 2 mL with 0.9% non-preserved sterile saline i.e. with a final diluted concentration of 50 U/mL. (a) For the 50 U total dose cohort the patients with the first injection regimen (1) will be injected with 0.5 mL of the diluted BOTOX on each side of the midline into the dorsal base of the penis (i.e. 25 U per injection site) and a total injection volume of 1 mL (total dose of 50 U divided in 2 injection sites); (b) For the 50 U total dose cohort the patients with the second injection regimen (2) will be injected both according to regimen (1) but only with 0.25 mL of the diluted BOTOX on each side into the proximal dorsal base of the penis (i.e. 12.5 U per injection site), as well as 0.25 mL of the diluted BOTOX on each side of the midline into the bulbuspongiosus muscles of the perineum (12.5 U per injection site) and a total injection volume of 1 mL (total dose of 50 U divided in 4 injection sites).
(67) The dilution for the 100 U dose cohort is a vial of 100 U diluted in 1 mL with 0.9% non-preserved sterile saline i.e. with a final diluted concentration of 100 U/mL. (a) For the 100 U total dose cohort the patients with the first injection regimen (1) will be injected with 0.5 mL of the diluted BOTOX on each side of the midline into the dorsal base of the penis (i.e. 50 U per injection site) and a total injection volume of 1 mL (total dose of 100 U divided in 2 injection sites); (b) For the 100 U total dose cohort the patients with the second injection regimen (2) will be injected both according to regimen (1) but only with 0.25 mL of the diluted BOTOX on each side into the proximal dorsal base of the penis (i.e. 25 U per injection site), as well as 0.25 mL of the diluted BOTOX on each side of the midline into the bulbuspongiosus muscles of the perineum (25 U per injection site) and a total injection volume of 1 mL (total dose of 100 U divided in 4 injection sites).
Example 2
(68) Treatment of Premature Ejaculation
(69) A male patient is diagnosed with premature ejaculation after presenting with climax times of less than 15 seconds after beginning sexual intercourse. The patient is treated with an effective amount of a botulinum toxin, BOTOX®.
(70) The doctor prepares the patient for injection by cleaning the patient's penis at the dorsal base with a skin disinfecting agent and subsequently applies topical lidocaine anesthesia cream or a local injection of lidocaine to anesthetize the area.
(71) Treatment consists of two injections (bilaterally) on both sides of the midline at the dorsal base of the penis. The injections are through the Superficial Fascia, into the area between the Bucks Fascia and the Tunica Albuginea, and in the proximity of the Pudendal nerve. The Pudendal nerve is targeted.
(72) 25 units of BOTOX® is injected at each injection site utilizing a 25 gauge needle for each injection, for a total of 50 units.
(73) Post procedure, the patient is instructed not to have sex during the following 48 hours. If edema and/or inflammation is noted, appropriate application of an ice-pack to the area is recommended (applied not longer than about 15 minutes at a time).
(74) At a follow up session 2 weeks later, the patient reports a doubling in his climax baseline time, with on some occasions lasting for about 10 to 15 minutes, and that both he and his partner are very satisfied with the resultant outcome of the treatment.