WO2014197137A1

WO2014197137A1 - Diversion-resistant formulation

Info

Publication number: WO2014197137A1
Application number: PCT/US2014/035768
Authority: WO
Inventors: Howard Brooks-Korn; David Alan LOWIN
Original assignee: Howard Brooks-Korn; Lowin David Alan
Priority date: 2013-04-29
Filing date: 2014-04-29
Publication date: 2014-12-11

Abstract

Diversion-resistant veterinary dosage forms and formulations for active agents have the potential for diversion and abuse by humans. A diversion-resistant veterinary formulation is provided, which includes an active agent that has the potential for diversion and abuse by humans, and an anti-diversive ingredient that is acceptable to a non-human animal for which the formulation is intended and unacceptable to a human being, where the anti-diversive ingredient is: a) an ingredient that is active in humans but not active in the non -human animal for which the formulation is intended; b) an ingredient to which humans are more sensitive than the non-human animal for which the formulation is intended, present in a human effective amount and less than an animal effective amount; or c) an ingredient formulated to remain biologically unavailable in the non-human animal for which the formulation is intended, but bioavailable when administered to a human.

Description

DIVERSION-RESISTANT FORMULATION

FIELD OF THE INVENTION

[001] This invention relates to formulations for the treatment of animals by the administration of an active agent that has the potential for diversion and abuse by humans.

BACKGROUND OF THE INVENTION

[002] U.S. Patent No. 8,410, 129 discloses the use of opiates for treatment of centrally and peripherally mediated neuropathies, polyneuropathies, disorders and syndromes including but not limited to lingual, pharyngeal, laryngeal, esophageal, urinary bladder sphincter, lumbar and lumbo-sacral spine, pelvis and pelvic-limb paresis/paralysis. This patent reports the successful reversal of paresis/paralysis in such disorders and syndromes, particularly by administering immediate or sustained release pharmaceutical formulations of hydrocodone, oxycodone and morphine sulfate, and teaches the similar use of other opioids. Particularly preferred among the opioids employed in the Ί 29 patent is oxycodone sustained release (OxyContin®) provided in the original formulation, e.g., as taught in U.S. Patent No. 5,508,042, which expired on April 16, 2013.

[003] On April 17, 2013 the United States Food and Drug Administration, citing concerns about prescription drug abuse, announced its decision not to approve generic versions of the original OxyContin formulation to the extent that such formulations are not abuse-deterrent. The originally marketed formulation for OxyContin had been changed by making it more difficult to crush, break or dissolve, and by including an ingredient that prevents it from being prepared for injection by turning into a sticky gel. Such abuse- deterrent formulations are described, for example, in U.S. Patent No. 8, 1 14,383 as including at least one hardening polymer and optionally at least one wax, along with at least one auxiliary substance selected from (a)-(f): (a) a substance that irritates the nasal passages and/or pharynx, (b) a viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid, (c) an antagonist for each of the active ingredients with abuse potential, (d) an emetic, (e) a dye, or (f) a bitter substance. The auxiliary substance(s) are taught to be present in a spatially separated arrangement from the other components of the dosage form, such that their effect would only manifest upon attempts to abuse the formulations, for example by breaking, cutting, crushing or dissolving. Regarding the use of an emetic, the '383 patent teaches the use of one or more constituents of radix ipecacuanha (ipecac root), preferably based on the constituent emetine. Auxiliary substances (c) and/or (d) and/or (f) are taught to be present in such a low dose that, when correctly administered, the dosage form is able to bring about virtually no effect which impairs the patient or the efficacy of the active ingredient. Emetine is taught to be present preferably in a quantity > 10 mg, particularly preferably > 20 mg, and very particularly preferably > 40 mg per dosage form.

[004] Expanding the use of opioids to veterinary indications gives rise to concerns regarding the potential for diversion of opiates intended for veterinary therapeutic use to abuse by humans. In general, this applies to any veterinary drug having the potential for diversion and abuse by humans. According to the US National Institute on Drug Abuse, the commonly abused prescription drugs include: depressants, opioids and morphine derivatives, stimulants, and dextromethorphan.

[005] Co-pending U.S. Applications Serial Nos. 1 1/395,200 and 1 1/395,242, and corresponding granted European Patent No. EP 2,007,388, further elucidate the Ί29 patent's teachings, particularly in view of the premise that abnormal concentrations of one or more endogenous opioids, or the blockade, underexpression or overexpression of one or more opioid receptors, can represent an underlying etiology of an ailment requiring treatment. Also disclosed are veterinary formulations responsive to the above-referenced concerns, including a "detractant" ingredient, for example, an odor, flavor, texture or other ingredient that while acceptable to a non-human mammal is unacceptable to a human being. In certain such formulations, the detractant could be considered a contaminant if included in a formulation intended for human consumption (e.g., hair, sand, insect parts or feces, treated to be non-harmful for a subject of the species for which the formulation is intended), but while feasible, the use of such detractants presents additional challenges to providing a veterinary product. Alternatively, such veterinary formulations can be manufactured in a dosage form that is unsuitable for human consumption, e.g., a chew bone. Such veterinary products can be prominently labeled to highlight the presence of the detractant as a warning against human consumption.

[006] It remains desired to provide a diversion-resistant veterinary formulation for an active agent that has the potential for diversion and abuse by humans, particularly wherein the formulation containis only accepted pharmaceutical and veterinary ingredients. SUMMARY OF THE INVENTION

[007] A diversion-resistant veterinary formulation is provided, which includes an active agent that has the potential for diversion and abuse by humans, and an anti-diversive ingredient that is acceptable to a non-human animal for which the formulation is intended and unacceptable to a human being, where the anti-diversive ingredient is:

a) an ingredient that is active in humans but not active in the non-human animal for which the formulation is intended;

b) an ingredient to which humans are more sensitive than the non-human animal for which the formulation is intended, present in a human effective amount and less than an animal effective amount; or

c) an ingredient formulated to remain biologically unavailable in the non-human animal for which the formulation is intended, but bioavailable when administered to a human.

[008] In one of its aspects, the anti-diversive ingredient causes an adverse reaction in the human but not in the animal for which the formulation is intended. Examples of such adverse reactions include, without limitation, nausea, emesis, pain, fever, puritis, rash, diarrhea and the like. One preferred group of nausea and/or emesis-causing anti-diversive ingredients includes ipecacuanha (ipecac or one of its active components, emetine and cephaeline), CCK8 and copper sulphate, particularly where the animal for which the formulation is intended is a dog. Active agents having the potential for diversion and abuse by humans include, without limitation, depressants, opioids and morphine derivatives, stimulants, and dextromethorphan. One particularly advantageous use of these formulations is for opiates, particularly oxycodone.

[009] Human effective amounts of ipecac can be in the range of about 0.001 mg/kg to about 0.1 mg/kg, or about 0.005 mg/kg to about 0.05 mg/kg. Thus, a veterinary formulation made to resist diversion assuming an average 70 kg human can include from about 0.07 mg to about 7.0 mg of ipecac. An alternative, more narrow human effective range is from about 0.35 mg to about 3.5 mg of ipecac. Formulations employing only emetine or cephaeline will use slightly lower effective amounts.

[010] A diversion-resistant canine veterinary formulation is disclosed, including: an active agent that has the potential for diversion and abuse by humans, and an anti- diversive ingredient to which humans are more sensitive than are dogs, the anti-diversive ingredient being present in a human effective amount and less than an animal effective amount and selected from the group: ipecac, emetine, cephaeline, CCK8 and copper sulphate. Such a formulation can be further formulated to release said anti-diversive agent at a pH characteristic of a quiescent human stomach, but lower than a mean of the pH of a quiescent canine stomach. [011] Another diversion-resistant canine veterinary formulation includes: an active agent that has the potential for diversion and abuse by humans, and ipecac in an amount sufficient to cause nausea and/or emesis in a human but insufficient to cause nausea and/or emesis in a dog. The diversion-resistant canine veterinary formulation can include from about 0.07 mg to about 7.0 mg of ipecac, preferably formulated for immediate release. Where the active agent that has the potential for diversion and abuse by humans is oxycodone, the formulation can include from about 10 mg to about 40 mg of oxycodone, preferably formulated for sustained release. The ipecac in such formulations can be formulated for release below a pH in the range of about 1 .6 to 2.0, or preferably to prevent release above about pH 1 .7.

DETAILED DESCRIPTION OF THE INVENTION

[012] Before describing the present invention in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Definitions

[013] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The singular form is intended to include the plural unless the context clearly dictates otherwise. For example, the term "an opioid compound" encompasses one or more opioids, as well as mixtures thereof.

[014] "Carriers" or "vehicles" as used herein refer to pharmaceutically and/or veterinarily accepted excipients known to be suitable for use in drug formulation and administration. Carriers and vehicles useful herein include, but are not limited to any such material known in the art, which is nontoxic and does not interact with other components of the composition in a deleterious manner.

[015] "Extended release" or "sustained release" is defined for purposes of the present invention as the rate at which a drug must be released after administration in order to maintain a therapeutically effective blood (plasma) level for a minimum of about 6 hours, but preferably lasting 12 to 36 hours or longer. This term is also employed to identify a formulation having such a release profile.

[016] "Immediate release" is defined for purposes of the present invention as the rate at which a drug must be released after administration in order to maintain a therapeutically effective blood (plasma) level for period of about 6 hours or less. This term is also employed to identify a formulation having such a release profile.

[017] The "non-human animal" for which the formulations of the present invention are intended include but are not limited to, mice, rats, ferrets, simians, farm animals, sport animals, and pets such as dogs and cats.

[018] By "human effective amount" is meant an amount of an anti-diversive ingredient in a quantity sufficient to provide a desired effect, e.g., causing nausea and/or emesis, in a human.

[019] By "animal effective amount" is meant an amount of an anti-diversive ingredient in a quantity sufficient to provide an undesired effect, e.g., causing nausea and/or emesis, in a non-human animal for which the formulation is intended.

[020] By "therapeutically effective amount" is meant a nontoxic amount of a drug, active agent or formulation in a quantity sufficient to provide a desired therapeutic effect, e.g., treatment of an ailment.

ACTIVE AGENTS

[021] Active agents having a potential for diversion and abuse by humans include, without limitation, depressants, opioids and morphine derivatives, stimulants (e.g., amphetamine/dextroamphetamine, dextroamphetamine and methylphenidate), and dextromethorphan. In a particular aspect of the invention, the active agent is an opiate, especially oxycodone (sustained or immediate release).

[022] Examples of opiates that can be used in the present invention include, but are not limited to: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, beta- hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diacetylmorphine (heroin), diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, LAAM, levallorphan, levorphanol, llevophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, O-methylnaltrexone, metopon, morphine, myrophine, nalbuphine, nalorphine, naloxone, naltrexone, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, remifentanil, sufentanil, tildine, tramadol, and the pharmaceutically acceptable salts thereof. Where an opiate agonist (such as oxycodone) is used, a very low dose of an opiate antagonist (such as naltrexone) can be included in the formulation to prevent tolerization.

[023] Active agents having the potential for diversion and abuse by humans can typically be administered by any suitable route. The present invention is predominantly concerned with oral administration and preventing the diversion of such veterinary products for use by humans whether orally or by crushing to circumvent sustained release, for inhalation, or for injection.

DIVERSION-RESISTANT FORMULATIONS

[024] The present invention provides veterinary formulations including a therapeutically effective amount of an active agent, an effective amount of an anti-diversive ingredient, and optionally a carrier. The formulations can include a mixture of two or more active agents and can be for immediate or sustained release. In addition to a carrier, the formulation can include adjuvants, diluents, buffers, other detractants and the like. Actual methods of preparing such dosage forms are well known or will be apparent to those skilled in the art. For example, see: Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995).

[025] The anti-diversive ingredient preferably causes an adverse reaction in the human, but not in the animal for which the formulation is intended. Examples of such adverse reactions include, without limitation, nausea, emesis, pain, fever, puritis, rash, diarrhea and the like. Preferred are anti-diversive ingredients that cause nausea and/or emesis. Nausea and/or emesis-causing anti-diversive ingredients include, without limitation, apomorphine, 1 ,2-dihydroxyaporphine, cisplatin, cholecystokinin octapeptide (CCK8), copper sulphate, cyclophosphamide, ipecacuanha (ipecac or either of it's active components, emetine and cephaeline), lithium chloride, morphine, nicotine, and rolipram. A preferred group of nausea and/or emesis-causing anti-diversive ingredients includes ipecacuanha (or emetine or cephaeline), CCK8 and copper sulphate.

[026] The anti-diversive ingredients of the present invention can be broadly characterized as suitable or acceptable to a non-human animal (for example, to dogs) but unsuitable or unacceptable to human beings. They can, however, be distinguished as an improvement over the detractants described in U.S. Applications Serial Nos. 1 1/395,200 and 1 1/395,242, in that such detractants were focused upon differential sensitivities between species (dogs and cats generally being attracted by a variety of strong odors, flavors and/or textures that are generally unpalatable to human beings) and upon human emotional reactions to detractants that could otherwise be viewed as contaminants in a formulation intended for humans, such as hair, sand, insect parts or even feces.

[027] One approach to providing an effective anti-diversive ingredient is to select an ingredient that is active in humans but not active in the non-human animal for which the formulation is intended. A second approach to providing an effective anti-diversive ingredient is to select an ingredient to which humans are more sensitive than the non- human animal for which the formulation is intended. A third approach to providing an effective anti-diversive ingredient is to formulate such an ingredient to remain biologically unavailable in the non-human animal for which the formulation is intended, but bioavailable when administered to a human. Combinations of these approaches can also be advantageously employed.

[028] Ipecac has long been known as an emetic. It is prepared from the dried rhizome and roots of the Cephalis acuminate or C. ipecacuanha plant. Its principal active ingredients are the ether-soluble alkaloids emetine and cephaeline (present in a ratio of approximately 0.8:1 .0, but, this ratio varies depending upon product and method of manufacture). It has most commonly been provided in the form of a syrup containing not less than 1.23 mg per ml. or more than 1.57 mg per ml. of the ether-soluble alkaloids in glycerin and can contain between 1.0% and 2.5% ethanol (USP). Typical emetic doses are 5 ml. - 10 ml. (children 6 to 12 months), 15 ml. (children 1 -12 years) and 15 - 30 ml_ (adolescents and adults); administration is typically preceded or followed by water.

[029] Syrup of ipecac was predominantly used to induce emesis for the removal of ingested poisons. Concerns have been raised regarding the usefulness of emesis as a treatment for poisoning, for example, in view of the following: toxin absorption between ingestion and induction of emesis, uncertainty that all of the toxin will be eliminated, re- exposure of sensitive throat and esophageal tissues to corrosive toxins, and the possibility of emesis aspiration.

[030] Other uses for syrup of ipecac have included treatment for cough and induction of emesis for weight loss (bulemia). Use by bulemics has been particularly discouraged, among other reasons because long-term use of syrup of ipecac can give rise to muscular and cardiac problems. Diarrhea, lethargy, drowsiness, and prolonged vomiting are the predominant adverse reactions associated with ipecac. Repeated exposure to powdered ipecac may cause rhinitis or asthma. It is further reported that ipecac extracts can be highly toxic, warning that the extracts should not be confused with syrup of ipecac. Emetine, used for over 100 years as a treatment for dysentery, can irritate skin if applied topically; it is a cardiotoxin and has been associated with serious cardiotoxicity (see, www.drugs.com/npp/ipecac.html).

[031] Syrup of ipecac was used to induce vomiting in dogs as reported in New Animal Drug Application 141-262 for approval of the antiemetic Cerenia (maropitant citrate) for the prevention of motion sickness in dogs. The dose confirmation study "Dose confirmation of the efficacy of CH-1 1 ,972 for syrup of ipecac (Ipecacuanha)-induced emesis in dogs" involved administration of syrup of ipecac (0.5 mL/kg) to Beagle dogs approximately one hour following administration of the test drug or placebo, followed by observation for emetic events (vomiting or retching). Dogs treated with the test drug showed fewer emetic events in dogs pre-treated with the test drug. The 0.5 mL/kg dosage corresponds to an animal effective amount in the range of 0.615 mg/kg to 0.785 mg/kg, or about 0.7 mg/kg (based on the 1.23 to 1 .57 mg per mL concentration specifications for syrup of ipecac). Thus, a formulation containing 7 mg of ipecac would be expected to cause nausea and/or emesis in a 10 kg dog; 14 mg of ipecac for a 20 kg dog and 28 mg for a 40 kg dog. These dosages are consistent with the absence of nausea and/or emesis with the significantly lower dosages employed in the formulations of the present invention.

[032] Particularly of interest in the present invention, the response to ipecac (ipecacuanha) is "very intense in humans but only weak in dogs" (Predicting the emetic liability of novel chemical entities: a comparative study, du Sert, et al., Br J Pharmacol, 2012 March; 165(6): 1848-1867.) The study reported by du Sert, et al., entailed a systematic review of publications identified from PubMed reporting experimental data on the use of ten emetic compounds, with the objective of comparing emetic compounds across species to investigate whether dogs, ferrets and rats are similarly predictive of humans. The ten emetic compounds are apomorphine, cisplatin, cholecystokinin octapeptide (CCK8), copper sulphate, cyclophosphamide, ipecacuanha, lithium chloride, morphine, nicotine, and rolipram. Of over 1000 publications reviewed, 31 1 reported quantitative data sufficient for inclusion in the study.

[033] As reported by du Sert, et al., humans are more sensitive to ipecacuanha, CCK8 and to copper sulphate than are dogs. Humans can display a response as intense as cisplatin-induced emesis following a dose of ipecac up to two orders of magnitude lower than the highest doses used in the dog. While a dose of 0.1 mg/kg is reported to elicit the full emetic response of cisplatin in the human, no emetic response is reported in the dog where a dose of about 1 .0 mg/kg results in only about 20% of the emetic response of cisplatin.

[034] Given this difference in sensitivities, a formulation intended to induce emesis in humans but not dogs can include 7.0 mg of ipecac, calculated as follows: 0.1 mg/kg for a typical 70 kg human = 7.0 mg; whereas 1 .0 mg/kg for a 20 kg dog = 20.0 mg, or for a 40 kg dog = 40 mg. Thus, a formulation containing a human effective amount of ipecac (or one of its ether-soluble alkaloids emetine and cephaeline), i.e., an amount effective to induce nausea and/or vomiting in the human, can contain significantly less than an animal effective amount of ipecac, i.e., an amount effective to induce nausea and/or vomiting in the dog. A human effective amount of ipecac can, e.g., be in the range from about 0.001 mg/kg to about 0.1 mg/kg, or about 0.005 mg/kg to about 0.05 mg/kg. At the upper limits, 20 mg/kg has been reported to constitute a toxic dose of emetine.

[035] The objectives to be accomplished by the use of anti-diversive ingredients in the present invention do not require causing an emetic response equal in intensity with that caused by cisplatin treatment. The anti-diversive effect need only cause sufficient discomfort to cause a human to avoid taking the diversion-resistant formulation (preferably via any route of administration); in that regard, substantially lower and safer amounts of anti-diversive ingredient can be employed. Thus, a human effective amount of ipecac that is less than an animal (i.e., canine) effective amount can be about 0.07 mg to about 7.0 mg, preferably about 0.35 mg to about 3.5 mg, or more specificaly about 0.5 mg to about 1 .5 mg, or even more specifically about 0.5 mg to about 1 .0 mg, or generally about 1 .0 mg for a typical 70 kg human.

[036] As noted in the '383 patent, a person skilled in the art will understand that the human effective amount and animal effective amount of anti-diversive ingredient may vary as a function of the particular ingredients used and of the formulation or the dosage form. The optimum formulation and effective amounts for a particular dosage form can be determined by simple preliminary testing.

[037] Alternatively, a variation of long acting, sustained release formulations employing pH dependent binders and coatings, e.g., as described in US Patent No. 5,209,933, can be employed in the present invention. An active agent having a potential for diversion and abuse by humans is formed into particles with a pH dependent binder, having substantially smooth, non-rugose surfaces which are coated with a coating material, preferably a coating material which is poorly soluble at about pH 4.5 and below, but readily soluble at, about pH of 5.5 and above. In contrast to conventional granules, which may be approximately spherical in their outermost surface dimensions, but are actually loose particulate aggregates with highly rugose surfaces and area radius to circumference radius ratios as taught in the '933 patent. The anti-diversive ingredient can be similarly bound, coated and formed into particles. In the case of anti-diversive ingredients functioning by virtue of being active in humans but not active in the non-human animal for which the formulation is intended and those to which humans are more sensitive, an effective amount can be formed into immediate release particles by selection of pH independent binders and coatings. Anti-diversive ingredients desired to remain biologically unavailable in the non- human animal for which the formulation is intended, but bioavailable when administered to a human, can be formed into particles, for example, employing a pH dependent coating that is insoluble in the animal but soluble in the human. As reported by Lui, et al., (Comparison of Gastrointestinal pH in dogs and Humans: Implications on the Use of the Beagle Dog as a Model for Oral Absorption in Humans, J. Pharm. Sci., Vol. 75, No 3, March 1986, 271 - 274) "[t]here was a statistically significant difference (p < 0.05) in quiescent gastric pH between dogs and humans. While the gastric pH in dogs was higher and exhibited a wider range, the variances were not significantly different." (Id. at 272.) These dififerences, while insignificant as regarding the predictiveness in canine models of oral absorption, can be employed to accomplish drug release in the stomach of the human but not the dog. Specifically, Lui, et al. (Figs. 2 and 3) show that pH in the quiescent human stomach ranges from about 2.0 to about 0.4 with a mean range of about 1.5 to about 0.75, whereas in the dog the pH in the quiescent stomach ranges from about 4.0 to about 0.5 with a mean range of about 2.0 to 1 .75. Thus, the anti-diversive ingredient of the present invention can be formulated to prevent release above a pH range of about 1 .6 to 2.0, preferably preventing release above about pH 1 .7 to facilitate making the anti-diversive ingredient available to the human but not the dog. Examples of formulations designed to effect release at specific pHs can be found in the literature, e.g., Balamuralidhara, et al., pH Sensitive Drug Delivery Systems: A Review, Am. J. Drug Discovery and Devel. 1 (1 ): 24-48, 201 1. The effective pH ranges can be confirmed for other breeds and/or species by measuring pH in the quiescent stomach. Utility of the species selectiveness of the present formulations can be directly tested in vivo.

[038] Particularly preferred is a diversion resistant formulation addressed to both differences in species sensitivity to the anti-diversive ingredient and differences in gastrointestinal pH. In this regard the diversion resistant formulation will contain an anti- diversive ingredient in a human effective amount that is less than an animal effective amount, protectively treated to release at the lower pH of a quiescent human stomach but not in the slightly higher pH of a quiescent canine stomach. One such preferred diversion resistant formulation contains an effective amount of oxycodone hydrochloride (e.g., 20 mg or 40 mg) formulated for sustained release, and a human effective amoiunt of ipecac (e.g., 0.35 mg to about 3.5 mg, or more specificaly about 0.5 mg to about 1 .5 mg, or about 1.0 mg.) formulated for immediate release at a pH characteristic of a quiescent human stomach, but lower than a mean pH of a quiescent canine stomach, e.g., below about pH 1.6 to 2.0, preferably preventing release above a pH of about 1 .7, and a veterinarily accepted carrier.

[039] It should be noted that the active agent and anti-diversive ingredient are preferably indistinguishable in order to prevent sorting to eliminate the anti-diversive ingredient for abuse.

[040] The formulations can include additional ingredients, veterinarily acceptable carriers, processing and/or packaging to render them tamper-resistant, to dissuade extraction and separation of the active agent(s) and thereby dissuade diversion or abuse. For example, such formulations can include excipients that maintain the effectiveness of the active agent, such that its extraction and/or separation of the active agent from one or more such ingredients of the formulation would render the agent unpalatable, less active or completely inactive. Detractants can be added to these formulations to render them unsuitable for use by other than the intended route of administration, e.g., adding capsaicin to a tablet in an amount that would not interfere with normal swallowing and absorption, but would dissuade misuse by snorting or dissolving the tablet for injection.

DOSAGE

[041 ] The amount of active agent administered will be dependent on the particular drug selected, the age and general condition of the subject being treated, the severity of the subject's condition, the dosing regimen and the judgment of the prescribing veterinarian. While daily dosing regimens can involve the administration of as many as eight doses, it is generally preferred that the number of doses be kept to a minimum for example to facilitate patient compliance. Moreover, the longer acting sustained-release dosage forms maintain a more consistent plasma concentration of the active agent, avoiding peaks and troughs.

[042] The lowest therapeutically effective dosage is the least amount of the pharmaceutical formulation sufficient to effect treatment. In the case of opioids administered for treating pain or paresis/paralysis, specifically oxycodone, for an animal subject weighing in the range of about 20 kg to about 40 kg, such as a dog, a starting dose of oxycodone sustained release can be about 10 mg to about 20 mg given every 12 hours. The dose of medication is adjusted according to the weight and need of a subject, to ameliorate the presenting symptoms. One of ordinary skill in the art will have the experience and means to determine the adjustment needed. Typically, if the symptoms have not started to resolve after about 2 to 14 days of treatment (or if a subject starts to show the symptoms of drug tolerance) the dose is elevated by a factor ranging from 1.25 to 2.0 times the original dosage (preferably 1 .5 times the original dose, e.g., 10 mg twice daily is increased to 15 mg twice daily) escalating on about a weekly basis until the symptoms are effectively treated at a well-tolerated dosage. Alternatively, to avoid breaking tablets, if no 5 mg. tablet is available the dose can be increased in 10 mg increments. Typically, the maximum dose of oxycodone sustained release administered to dogs has been 40 mg twice daily. The highest tolerated dosage is the maximum amount of the pharmaceutical formulation to effect treatment without the occurrence of adverse side effect(s) outweighing the benefit received. If the subject's highest tolerated dosage is reached, treatment should be discontinued, optionally re-commencing treatment by substituting a different active agent or formulation.

[043] The dose employed for the anti-diversive ingredient of the invention will preferably be the lowest human effective dose shown to work in a statistically significant portion of human volunteers tested with a given formulation, and in any case lower than the animal effective dose. As discussed above with reference to ipecac, such an effective dose can be as much as about 0.1 mg/kg; effective doses can be as low as about 0.01 mg/kg or even 0.001 mg/kg. TESTING

[044] Clinical assessments of nausea can be performed by counting emetic events (vomiting or retching) and by observation of increased salivation, lip licking, frequent and/or exaggerated sallowing motions, lethargy, restlessness and/or panting. The observations are quantified using a Visual Analog Scale (VAS). Degree of nausea is quantified by drawing a single vertical line to intersect a 100 millimeter horizontal line. The distance in millimeters from this intersection to the left origin of the VAS represents the severity of nausea. A score of zero is defined as no nausea and a score of 100 is defined as the worst possible nausea. (See, NADA 141-262.)

[045] Testing for nausea in humans can employ similar observations, but can also be far more direct in that the human volunteer test subject can verbally report on the degree of nausea (if any) being experienced.

[046] In the testing of the instant formulations, the formulation or a control having no anti-diversive ingredient is administered to a group of test animals and to a group of human volunteer test subjects sufficiently large to provide reliable (e.g., statistically significant) results confirming that the amount of anti-diversive ingredient causes the intended response in humans but not in animals in the particular formulation. The evaluation can be initially conducted using formulations without any active agent, so the effectiveness of the amount of anti-diversive ingredient can be determined without exposing the test subjects to an active agent having the potential for diversion and abuse by humans. The evaluation can then be repeated using a formulation including such an active agent.

[047] Additional testing can be conducted, for example, as discussed in the FDA document "Guidance for Industry Abuse-Deterrent Opioids - Evaluation and Labeling" (Januarty 2013, incorporated herein by reference). Such additional testing can include laboratory-based in vitro manipulation and extraction studies (e.g., to demonstrate impracticality of separating the active agent from the anti-diversive ingredient), pharmacokinetic studies, and clinical abuse potential studies (e.g., using a VAS to measure drug liking, good effects, bad effects and other drug abuse-related effects to show effectiveness in lowering the potential for abuse). It should be noted that the FDA document was addressed to formulations intended for use by humans (as opposed to preventing abuse by humans of a formulation intended for veterinary use). Thus, for example, clinical abuse potential studies can be designed to compare drug liking of available human formulations against the instant veterinary formulations, and drug liking of veterinary formulation with and without the anti-diversive ingredient. It should also be noted that the FDA document was distributed as a draft; final guidance has yet to be issued. EXAMPLES

[048] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes.

Example 1

Extended Release Tablet Formulation

[049] 1A. This example illustrates the preparation of a representative veterinary formulation for oral administration containing oxycodone hydrochloride and ipecac, for example, as described in US Patent No. 5,508,042. See Table 1 .

[050] Eudragit® RS 30D and Triacetin® are combined while passing through a 60 mesh screen, and mixed under low shear for approximately 5 minutes or until a uniform dispersion is observed. The oxycodone HCI, lactose and povidone are placed into a fluid bed granulator/dryer (FBD) bowl, and the previously obtained suspension is sprayed onto the powder in the fluid bed. After spraying, the granulation is passed through a #12 screen if necessary to reduce lumps. The dry granulation is placed in a mixer, to which stearyl alcohol (previously melted at about 70°C) is added with mixing. The resulting waxed granulation is transferred to a fluid bed granulator/dryer or to trays, and allowed to cool to room temperature or below, followed (if necessary) by passage through a #12 screen. Thereafter, the waxed granulation and Ipecac are placed in a mixer/blender and lubricated with the required amounts of talc and magnesium stearate for approximately 3 minutes, and then the granulate is compressed into 125 mg tablets on a suitable tableting machine.

Table 1

Ingredient Amount/Tablet Amount/

% (by wt)

1000 Tablet Batch

Oxycodone Hydrochloride 20.0 mg 16.0 % 20.0 g

Eudragit ® RS 30D (solids) 10.0 mg 8.0 % 10.0 g

Triacetin® 2.0 mg 1.6 % 2.0 g

Lactose USP (spray dried) 58.25 mg 46.6 % 58.25 g

Povidone 5.0 mg 4.0 % 5.0 g

Stearyl Alcohol 25.0 mg 20.0 % 25.0 g

Ipecac (powder) 1 .0 mg 0.8 % 1 .0 g

Talc 2.5 mg 2.0 % 2.5 g

Magnesium Stearate 1.25 mg 1.0 % 1.25 g

Total: 125.0 mg 100.0 % 125.0 g [051] 1 B. In the formulation of Example 1A, the ipecac is substituted by a human effective amount of emetine, cephaeline, CCK8 and/or copper sulphate.

[052] 1C. In the formulation of Example 1A or 1 B, the oxycodone hydrochloride is substituted by an therapeutically effective amount of buprenorphine, codeine, fentanyl, hydrocodone, meperidine, morphine sulfate, amphetamine/dextroamphetamine, dextroamphetamine, methylphenidate or dextromethorphan.

[053] 1 D. In the formulation of Example 1A, the ipecac is formed into granules and coated to prevent release above pH 1.7, and then added to the waxed granulation when it is placed in the mixer/blender, lubricated with talc and magnesium stearate and compresssed into tablets.

[054] 1 E. The formulation of Example 1A is prepared with the addition of a therapeutically effective amount of naltrexone.

Example 2

Packaged Veterinary Product

[055] 2. A quantity (30 units) of a veterinary formulation of Example 1A is sealed in one or more blister packs marked for twice-daily administration. The blister packs are placed in a package labeled as follows:

"Canine Oxycodone Hydrochloride Sustained Release, 20 mg

WARNING - CONTAINS IPECAC

PRODUCES INTENSE NAUSEA AND VOMITING IN HUMANS NOT FOR HUMAN CONSUMPTION"

Example 3

Emesis Testing

[056] 3A. Three batches of test formulations are prepared as described in Example 1 , containing 0 mg, 0.5 mg and 1.0 mg of ipecac, respectively. Each test formulation contains no oxycodone hydrochloride; reduction of oxycodone hydrochloride and ipecac % wt is adjusted for by increasing the amount of excipients.

[057] 3B. 24 Beagle dogs (12 sexually intact males and 12 sexually intact females) approximately 7 months old, weighing between 5 and 10 kg are randomized into three groups (of 4 males and females, each). To the subjects of each group are administered one tablet (containing 0 mg, 0.5 mg or 1.0 mg of ipecac, respectively). For one hour following administration, each subject is monitored for emetic events (vomiting or retching) and by observation of increased salivation, lip licking, frequent and/or exaggerated sallowing motions, lethargy, restlessness and/or panting. The results are quantified using a Visual Analog Scale (VAS). [058] 3C. 24 Healthy adult human volunteers (12 males and 12 females) are randomized into three groups (of 4 males and females, each). To the subjects of each group are administered one tablet (containing 0 mg, 0.5 mg or 1 .0 mg of ipecac, respectively). For one hour following administration, each subject is monitored for emetic events (vomiting or retching). The subjects each report the degree of nausea (if any) being experienced at ten-minute intervals during the hour. The results are quantified using a Visual Analog Scale (VAS).

[059] 3D. The results from all three groups of dogs of Example 3B show the absence of emetic events. The results from the human groups of Example 3C show no nausea or emetic events in the group receiving 0 mg of ipecac, but nausea and emetic events are shown in the groups receiving 0.5 mg and 1.0 mg of ipecac. Formulations containing low doses of ipecac cause nausea in humans but not in dogs.

Example 4

Emesis Testing

[060] 4A. Three batches of test formulations are prepared as described in Example 1 , containing 0 mg, 0.5 mg and 1.0 mg of ipecac, respectively. Each test formulation contains 10 mg oxycodone hydrochloride; reduction of oxycodone hydrochloride and ipecac % wt is adjusted for by increasing the amount of excipients.

[061] 4B. 24 Beagle dogs (12 sexually intact males and 12 sexually intact females) approximately 7 months old, weighing between 5 and 10 kg are randomized into three groups (of 4 males and females, each). To the subjects of each group are administered one tablet (containing 0 mg, 0.5 mg or 1 .0 mg of ipecac, respectively). For one hour following administration, each subject is monitored for emetic events (vomiting or retching) and by observation of increased salivation, lip licking, frequent and/or exaggerated sallowing motions, lethargy, restlessness and/or panting. The results are quantified using a Visual Analog Scale (VAS).

[062] 4C. 24 Healthy adult human volunteers (12 males and 12 females) are randomized into three groups (of 4 males and females, each). To the subjects of each group are administered one tablet (containing 0 mg, 0.5 mg or 1 .0 mg of ipecac, respectively). For one hour following administration, each subject is monitored for emetic events (vomiting or retching). The subjects each report the degree of nausea (if any) being experienced at ten-minute intervals during the hour. The results are quantified using a Visual Analog Scale (VAS).

[063] 4D. The results from all three groups of dogs of Example 4B show the absence of emetic events. The results from the human groups of Example 4C show no nausea or emetic events in the group receiving 0 mg of ipecac, but nausea and emetic events are shown in the groups receiving 0.5 mg and 1.0 mg of ipecac. Formulations containing low doses of ipecac cause nausea in humans but not in dogs.

Example 5

Abuse Potential Testing

[064] 5A. Three batches of test formulations are prepared as described in Example 1 , containing 0 mg, 0.5 mg and 1.0 mg of ipecac, respectively. Each test formulation contains 20 mg oxycodone hydrochloride; reduction of ipecac % wt is adjusted for by increasing the amount of excipients.

[065] 5B. 32 Opioid-experienced abuser human volunteers who are not physically dependent and are not seeking or participating in treatment for drug abuse (16 males and 16 females) are randomized into four groups (of 4 males and females, each). To the subjects of each of three groups are administered one tablet (containing 0 mg, 0.5 mg or 1.0 mg of ipecac, respectively) of the formulations prepared in Example 5A. To the subjects of the fourth group are administered one tablet of commercially available OcyContin (20 mg). For one hour following administration, each subject is monitored for emetic events (vomiting or retching). The subjects each report the degree of nausea (if any) being experienced as well as drug liking, good effects, bad effects and other drug abuse-related effects, at ten-minute intervals during the hour. The results are quantified using a Visual Analog Scale (VAS).

[066] 5C. The subjects who receive commercial OxyContin (20 mg) and who receive the formulation prepared in Example 5A containing 0 mg of ipecac (the "control subjects") show no nausea or emetic events and report positively for drug liking and good effects. The subjects who receive the formulation prepared in Example 5A containing 0.5 mg or 1 .0 mg of ipecac show nausea and emetic events, report less positively for drug liking and good effects as compared with the control subjects and complain of bad effects from the formulation. The formulation of the present invention demonstrates lowered abuse potential.

[067] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All patents and publications (including websites) cited above are hereby incorporated by reference.

Claims

We claim:

1. A diversion-resistant veterinary formulation comprising: an active agent that has the potential for diversion and abuse by humans, and an anti-diversive ingredient that is acceptable to a non-human animal for which the formulation is intended and unacceptable to a human being, said anti-diversive ingredient being selected from:

2. The diversion-resistant veterinary formulation of Claim 1 wherein said anti-diversive ingredient causes an adverse reaction in the human but not in the animal for which the formulation is intended.

3. The diversion-resistant veterinary formulation of Claim 1 wherein said anti-diversive ingredient is selected from the group: ipecac, emetine, cephaeline, CCK8 and copper sulphate.

4. The diversion-resistant veterinary formulation of Claim 3 wherein said non-human animal is a dog.

5. The diversion-resistant veterinary formulation of Claim 3 wherein said anti-diversive ingredient is present in a human effective amount and less than an animal effective amount.

6. The diversion-resistant veterinary formulation of Claim 5 wherein said anti-diversive ingredient is ipecac and said human effective amount about 1.0 mg.

7. The diversion-resistant veterinary formulation of Claim 6 wherein said non-human animal is a dog.

8. The diversion-resistant veterinary formulation of Claim 1 wherein said anti-diversive ingredienty is formulated to remain biologically unavailable in the non-human animal for which the formulation is intended, but bioavailable when administered to a human.

9. The diversion-resistant veterinary formulation of Claim 1 wherein said active agent having the potential for diversion and abuse by humans is selected from the group: depressants, opioids and morphine derivatives, stimulants, and dextromethorphan.

10. A diversion-resistant canine veterinary formulation comprising: an active agent that has the potential for diversion and abuse by humans, and an anti-diversive ingredient to which humans are more sensitive than are dogs, said anti-diversive ingredient being present in a human effective amount and less than an animal effective amount and selected from the group: ipecac, emetine, cephaeline, CCK8 and copper sulphate.

1 1 . The diversion-resistant canine veterinary formulation of Claim 10 formulated to release said anti-diversive agent at a pH characteristic of a quiescent human stomach, but lower than a mean pH of a quiescent canine stomach.

12. A diversion-resistant canine veterinary formulation comprising: an active agent that has the potential for diversion and abuse by humans, and ipecac in an amount sufficient to cause nausea and/or emesis in a human but insufficient to cause nausea and/or emesis in a dog.

13. The diversion-resistant canine veterinary formulation of Claim 12 comprising about 0.07 mg to about 7.0 mg of ipecac.

14. The diversion-resistant canine veterinary formulation of Claim 13 comprising about 10 mg to about 40 mg of oxycodone.

15. The diversion-resistant canine veterinary formulation of Claim 14 wherein said oxycodone is formulated for sustained release.

16. The diversion-resistant canine veterinary formulation of Claim 15 wherein said ipecac is formulated for immediate release.

17. The diversion-resistant canine veterinary formulation of Claim 12 wherein said ipecac is formulated for release below about pH 1.6 to 2.0.

18. The diversion-resistant canine veterinary formulation of Claim 12 wherein said ipecac is formulated to prevent release above a pH of about 1 .7.

19. The diversion-resistant canine veterinary formulation of Claim 12 wherein said active agent is oxycodone.

20. The diversion-resistant canine veterinary formulation of Claim 19 comprising about 0.5 mg to about 1 .0 mg of ipecac.