Patent Application
20230414644
The teachings of this disclosure generally relate to a spinosyn, a canine feed that includes the spinosyn and a method of administering the spinosyn in a feed to control flea infestations in canines.
Dog ownership has increased globally. Around 471 million dogs are kept as household pets. The most common ectoparasites of dogs worldwide are the cat and dog fleas, Ctenocephalides felis felis and Ctenocephalides canis, respectively. Flea-related infestations are among the leading causes of dermatological issues for canines reported to veterinarians. In addition, the cat flea is known to transmit tapeworms in dogs and has been implicated in the transmission of cat scratch disease and murine typhus as well.
The health related risks of flea infestations in dogs extend to humans. [Center for Disease Control and Prevention, Illnesses on the Rise, Vital Signs, May, 2018, available at https://www.cdc.gov/vitalsigns/vector-borne/] Infested canines expose their human owners to increased risk of illness. One of the recommended ways to control human risk from fleas is to control the risk of infestation in dogs.
Treatments currently available for controlling flea infestations in canines achieve varying degrees of success. Many treatments involve chemicals applied to indoor and outdoor surfaces, as well as to the canine. The chemicals used include a variety of carbamates, pyrethrins and pyrethroids, isoxazolines, certain macrocyclic lactones, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles or fiproles. These compounds often have toxic side effects that are a problem for both the canine and its owner. In addition, there is evidence that the use of these chemicals may be ineffective due to insecticide resistance and treatment deficiencies. [M. K. Rust, The Biology and Ecology of Cat Fleas and Advancements in Their Pest Management: A Review, Insects 2017, 8 118.].
Topical treatments are a well-known method for controlling flea infestations in canines. While there are numerous ways to deliver these therapeutic agents to the coats and skins of canines, many of these methods are either ineffective and/or present safety risks to the canine or user during or after the dispensing activity. More particularly, because a physical connection must be achieved between the applicator tip and the drug delivery device when the applicator tip is installed thereon, there is inherently a risk that the connection will be inadequate, thereby permitting some of the therapeutic agent to leak out of the device and into physical contact with the user. For example, in the case of larger canines, it may be difficult to maneuver the dispenser with one hand and maintain the canine in place with the other hand, resulting in some, if not all, of the substance being spilled on the floor or on the person applying it instead of reaching the canine's skin. Not only is this leakage wasteful and messy, it also places the user at a heightened risk of suffering from a skin irritation or other such health concern, particularly if the user comes into direct contact with the agent.
Oral treatments are also available. However, to be effective, the canine owner must administer a treatment once every 30-90 days, for example. The extended time between treatments creates compliance issues when owners forget to administer doses.
Despite the availability of effective treatments, a recent study by The Harris Poll found that 33% of pet owners do not routinely protect their pets against fleas at all. Another study found that pet owners purchased, on average, only 4 months of flea prevention products per year per pet, despite being told that pets needed to be given flea prevention treatments year-round. Thus, there continues to be a need for relatively safe, effective agents for controlling flea infestations on canines that are easier for owners to remember to use.
Surprisingly, it has been discovered by the inventors that spinosyns, such as spinosad, can provide improved control over flea infestations in canines when orally administered in smaller, more frequent/chronic doses. The administration is discussed below as being combined with feed. However, it is also contemplated that the spinosyn may be administered by itself or in a dosage form other than feed, such as a chew, tablet, liquid, gel or other suitable form for oral administration. Advantageously, by using smaller, more frequent doses, less total active material is required over the same time period to control flea infestations. Assume, for example, that 30 mg of spinosyn/kg of canine body weight is needed for a single dose in a 30-day (1-month) period according to the prior art approach to reach and maintain a therapeutically effective concentration of spinosyn in the canine's blood for continued flea control. With the inventive approach of smaller and more frequent doses, as little as 0.16-0.83 mg of spinosyn/kg of canine body weight may be needed per day, or 5-25 mg of spinosyn/kg of canine body weight cumulative over the same 30-day period.
Advantageously, the total amount of spinosyn required for a therapeutically effective once-monthly dose can be reduced by 10-87.5% by converting to daily administration. However, from a practical perspective, at least two problems arise: (1) creating a homogenous feed; and (2) analytical control testing for a very small dose of spinosyn may be difficult to accomplish. The analytical matrix from feeds can be quite complex and difficult to assay. Assays will be in the parts per million to billion range for some needed dose and feed concentrations. Thus, it is possible that one of skill in the art may opt to increase the daily dose such that the total of the daily doses over the course of one month equals the prior art once-monthly dose or is even higher, for example, 200% of the prior art once-monthly dose. This may be done to help ensure homogeneity as well as increase assay accuracy and decrease analytical variability when administering the dose as part of a daily feed.
The method and composition taught herein have the further advantage of encouraging compliance because the smaller doses of a spinosyn can be incorporated into a feed. Since owners naturally follow a daily feeding regimen in any event, this makes it less likely that owners will forget or neglect to administer the spinosyn. Thus, this disclosure provides a method for prolonged control of fleas in a safer and more effective manner than that achieved with previously known treatment methodologies. All the owner need remember is to feed their pet as they normally would.
Spinosyns are naturally derived fermentation products. They are macrolides produced by cultivation of Saccharopolyspora spinosa. The fermentation of S. spinosa produces many factors, including spinosyn A and spinosyn D (also called A83543A and A8354D). Spinosyn A and spinosyn D are the two spinosyns that are most active as insecticides. A product comprised mainly of these two spinosyns is available commercially under the generic name “spinosad”. The major spinosyn factor, spinosyn A, is particularly known to have an excellent human and canine safety and toxicological profile.
Each spinosyn has a 12-membered macrocyclic ring that is part of an unusual tetracyclic ring system to which two different sugars are attached, the amino-sugar forosamine and the neutral sugar 2N,3N,4N-(tri-O-methyl)rhamnose. This unique structure sets the spinosyns apart from other macrocyclic compounds.
Spinosyn A was the first spinosyn isolated and identified from the fermentation broth of S. spinosa. Subsequent examination of the fermentation broth revealed that S. spinosa produced a number of spinosyns that have been called spinosyns A to J (A83543A to J). The primary components are spinosyns A and D. Additional spinosyns, lettered from K to W, have been identified from mutant strains of S. spinosa. The various spinosyns are characterized by differences in the substitution patterns on the amino group of the forosamine, at selected sites on the tetracyclic ring system and on the 2N,3N,4N-(tri-O-methyl)rhamnose group.
Boeck et al. described spinosyns A-H and J (which they called A83543 factors A, B, C, D, E, F, G, H and J), and salts thereof, in U.S. Pat. No. 5,362,634 (issued Nov. 8, 1994); U.S. Pat. No. 5,496,932 (issued Mar. 5, 1996); and 5,571,901 (issued Nov. 5, 1996). Mynderse et al. described spinosyns L-N (which they called A83543 factors L, M and N), their N-demethyl derivatives, and salts thereof, in U.S. Pat. No. 5,202,242 (issued Apr. 13, 1993); and Turner et al. described spinosyns Q-T (which they called A83543 factors Q, R, S and T), their N-demethyl derivatives, and salts thereof, in U.S. Pat. No. 5,591,606 (issued Jan. 7, 1997) and 5,631,155 (issued May 29, 1997). Spinosyns K, O, P, U, V, W and Y are described, for example, by Carl V. DeAmicis, James E. Dripps, Chris J. Hatton and Laura I. Karr in American Chemical Society's Symposium Series: Phytochemicals for Pest Control, Chapter 11, “Physical and Biological Properties of Spinosyns: Novel Macrolide Pest-Control Agents from Fermentation”, pages 146-154 (1997).
The spinosyns can react to form salts that are also useful in the methods and formulations of this disclosure. The salts are prepared using standard procedures for salt preparation. For example, spinosyn A can be neutralized with an appropriate acid to form an acid addition salt. The acid addition salts of spinosyns are particularly useful. Representative suitable acid addition salts include salts formed by reaction with either an organic or inorganic acid such as, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, glutamic, camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic and like acids.
The term “spinosyn” as used herein refers to an individual spinosyn factor (spinosyn A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y), an N-demethyl derivative of an individual spinosyn factor, a chemically modified spinosyn such as spinetoram, a salt of any of the aforementioned, a metabolite of any of the aforementioned, a physiologically acceptable derivative thereof, or a combination thereof.
Spinosyns also provide advantages because they are very effective against fleas with post-treatment residual protection, when the dosages described herein are used. Furthermore, spinosyns have no insecticidal cross-resistance to existing compounds. Thus, they are especially useful against flea populations on canines that have existing levels of resistance to currently used products. Spinosyns, therefore, can be used in integrated pest management (IPM) programs to extend the lifeline of commonly used products where resistance is not well developed or has not yet developed.
Systemic efficacy (e.g., ingestion of blood containing spinosyns by fleas) provides a different mode of exposure compared to topically applied formulations where contact with the flea at the skin surface is the mode of exposure. The advantages of oral systemic treatments and killing of fleas from their ingestion of blood, compared to topical applications and contact killing, include:
The formulations, or feeds, and methods of this disclosure may further include, in combination with the spinosyn, one or more other active substances having therapeutic efficacy. Such active substances include agents efficacious against fleas. Active substances may include, for example, isoxazolines, foramidines, certain macrocyclic lactones, insect growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles or fiproles.
The methods of this disclosure are carried out by administering the spinosyn to the canine in small, frequent doses. To facilitate routine dosing, the spinosyn administration may be carried out using a feed. A number of different feeds are envisioned, provided the manufacturing process(es) and feed compositions do not have deleterious effects related to chemical stability, efficacy and safety on the spinosyn and, if applicable, other active substances. For example, feeds in the broad categories of dry, semi-moist, canned-retorted feeds, a treat, snack or other supplemental feed, or fresh refrigerated feeds may be adapted for use with this disclosure. The canine receives a maintenance quantity of spinosyn by consuming the feed product on a weekly, semi-weekly or daily basis.
By incorporating smaller doses of spinosyn into an animal feed composition and administering it at an effective rate (most preferably daily), the blood level of the spinosyn rises over time until it reaches an optimal steady state where it can be maintained by a daily or substantially daily dosage. By contrast, when a spinosyn is orally administered in larger doses at lower frequency, e.g., a single treatment of a large dose that is administered via “treat” once in a 30-day period, the level of the spinosyn in the blood spikes at the time of the dose and then declines until the next dose is administered. The administration of a large dose at low frequency means that the canine must consume more spinosyn in each dose so that the blood level of the spinosyn does not fall below the necessary level for effective protection before the next dose.
All ratios, percentages, and parts discussed herein are “by weight” unless otherwise specified.
The term “controlling a flea infestation” refers to preventing, treating, minimizing or eliminating an infestation by fleas on a canine.
The term “flea” refers to any member of the order Siphonaptera. The term “flea” includes the egg, larval, pupal, and adult stages of development.
The term “canine” refers to any member of the genus Canis, which includes such species as wolves, dogs, coyotes and jackals.
In carrying out the methods of this disclosure, a “feed” is an animal feed or treat, snack or other supplemental feed that may be administered daily or substantially daily. By using different forms of feed, e.g., kibble and treats or chews, a pet owner may vary the canine's meals and snacks from time to time while still conveniently administering a daily dose of spinosyn.
The term “chew” refers to a treat that has flavor and aromatic properties that are appealing to a canine, but typically has no nutritional value. In carrying out the methods of this disclosure, a “feed” and/or a “chew” may be used interchangeably.
The term “effective time”, also referred to herein as “effective duration”, for the purposes of this disclosure includes at least the duration of administration needed to bring the level of spinosyn in the canine's blood to a sufficiently high level for controlling fleas, i.e., a “therapeutically effective” level. In some embodiments, the effective time may be as little as three days. In other instances, the effective time may be seven days or fifteen days or longer. As discussed below, the effective time will vary based on how frequently the spinosyn is administered.
As just alluded, the “effective time” will vary as a function of the frequency at which the spinosyn is administered. The term “effective frequency” as used herein means the number of administrations over a given time that produce a therapeutically effective concentration of spinosyn in the canine's blood. In all events, the term “effective frequency” as used herein contemplates multiple administrations including the spinosyn per month. One of skill in the art will appreciate that the spinosyn may be administered in a range of frequencies. For example, the spinosyn may be administered at a frequency of daily, every other day, every third day, once per week or even at inconsistent time intervals.
Further, as discussed above, the effective frequency may affect the duration required to obtain a therapeutically effective level of spinosyn in the canine's blood. By way of example, if the canine were being given the spinosyn daily, the duration of administration required to achieve a therapeutically effective level of spinosyn in the canine's blood, and thus the “effective time”, would be comparatively less than if the canine were being given the spinosyn only once or twice per week.
Further, the effective frequency is influenced by the amount of the daily dose in mg/kg of body weight of the canine. Particularly, at slightly higher daily doses, e.g., greater than 1.0 mg/kg, missed doses have less of an impact on efficacy.
Further, the effective frequency is influenced by the duration of treatment. In the initial stages, i.e., before the amount of spinosyn in the canine's blood has reached a therapeutically effective level, the spinosyn, or feed, may need to be administered at a greater frequency than would be necessary if it were being administered after a longer period of use, i.e., once a therapeutically effective level is obtained.
For purposes of this disclosure, “substantially daily” means a sufficiently regular basis such that the spinosyn concentration in the canine's blood rises to and remains at a therapeutically effective level. For example, the disclosed feed composition can preferably be fed to a canine every day indefinitely. However, as a practical matter, there are many reasons why days may be missed or skipped periodically. For example, the canine may be ill or the owner may run out of the medicated feed composition. The disclosed method is robust enough that the canine will still be protected from fleas to some extent even with occasional interruptions in daily feeding of the medicated animal feed composition. In carrying out the method of this disclosure, the term “substantially daily” includes at least 10 days per month, more preferably at least 15 days per month, still more preferably at least 20 days per month. All of these administration frequencies, whether they be, e.g., three times per week, every other day or daily, fit under the umbrella of “substantially daily” provided that they promote the spinosyn reaching and maintaining a therapeutically effective level in the canine's blood.
The term “therapeutically effective” means that the dose or blood level of a spinosyn or a physiologically acceptable derivative thereof, or a metabolite thereof, is sufficient to control the flea infestation better than if no drug were present. The spinosyn or a physiologically acceptable derivative thereof, or a metabolite thereof, may be present on its own or with one or more additional active substances. Preferably it controls the flea infestation at around at least 50% better than if no drug were present, and more preferably it controls the flea infestation at about at least 90% better than if no drug were present.
In carrying out the methods of this disclosure, an effective or therapeutically effective amount of a spinosyn is administered orally to the canine. The term “effective amount” or “therapeutically effective amount” refers to the amount needed to control the flea infestation. As those skilled in the art will understand, this amount will vary depending upon a number of factors. These factors include, for example, the type of canine being treated and its weight and general physical condition.
While this disclosure describes concentrations of spinosyn in terms of feeds such as kibble, it also contemplates administration using other dosage forms, such as treats or chews. It is also contemplated that the spinosyn may be administered by itself or in a tablet, liquid, gel or other suitable form for oral administration. One of skill in the art will appreciate that the concentration of spinosyn will vary according to the particular dosage form. For example, where the dosage form is a treat or chew, the concentration of spinosyn in the treat or chew will be greater than, e.g., the concentration of spinosyn in kibble. For example, if the daily dose of spinosyn based on the weight of the canine is then a typical 5 g treat or chew would contain about 0.2 percent spinosyn (by weight). Since the amount of kibble consumed in a day is more than 5 g, the percent spinosyn in kibble will be smaller.
In general, an effective amount refers to a dose of from about 0.125 to about mg of the spinosyn/kg of body weight of the canine. More preferably, an effective amount refers to a dose of from about 0.2 to about 4.5 mg of the spinosyn/kg of body weight of the canine. More commonly, the effective amount is from about 0.2 to about 3.75 mg/kg of body weight of the canine.
Animal feeds will typically contain from about 0.0005 to about 0.2 percent of the spinosyn (by weight) in the feed; preferably between about 0.001 to about 0.12 percent of the spinosyn (by weight) in the feed; most preferably between about 0.003 to about 0.06 percent of the spinosyn (by weight) in the feed.
In one aspect, this disclosure relates to a method of controlling a flea infestation in a canine by administering a systemically active oral composition including spinosyn, or a physiologically acceptable derivative or salt thereof, at least once per week, more preferably three times per week, most preferably substantially daily.
In another aspect, this disclosure relates to a systemically active oral composition that includes a spinosyn and animal feed.
This disclosure also relates to the use of a spinosyn for the manufacture of an animal feed for controlling a flea infestation on a canine.
This disclosure also relates to a method of controlling a flea infestation on a canine for a prolonged time, comprising orally administering daily or substantially daily doses of an effective amount of a spinosyn to the canine in, e.g., a feed. A daily feed is a feed that is intended to be administered daily, but which may be administered less frequently than daily, as described herein. This method is especially useful for controlling fleas on a canine for a prolonged time comprising orally administering substantially daily doses of an effective amount of a spinosyn to the canine.
An aspect of this disclosure is the oral administration of an amount of spinosyn which is, in and of itself, ineffective or sub-optimal for controlling a flea infestation in a canine in a single dose, but over time with repeated administrations, as described herein, results in efficacious control of flea infestations. Ineffective or sub-optimal means that a single dosing, as well as several dosings, results in less than a 50% reduction in the flea infestation, including no, or substantially no, reduction, as compared to no drug administration at all. This reflects the chronic, rather than acute, administration aspect disclosed herein.
In an aspect of any of the embodiments, administration for controlling a flea infestation maintains a concentration of spinosyn of at least 5 ng/ml and not more than 600 ng/ml in said canine's blood for at least 30 days. More preferably, administration maintains a concentration of spinosyn of at least 5 ng/ml and not more than 300 ng/ml in said canine's blood for at least 30 days. More preferably, administration maintains a concentration of spinosyn of at least 10 ng/ml and not more than 225 ng/ml in said canine's blood for at least 30 days. Still more preferably, administration maintains a concentration of spinosyn of at least 25 ng/ml and not more than 200 ng/ml in said canine's blood for at least 30 days.
In an aspect of any of the embodiments, administration for controlling a flea infestation maintains a concentration of spinosyn of at least 5 ng/ml and not more than 600 ng/ml in said canine's blood for at least 365 days. More preferably, administration maintains a concentration of spinosyn of at least 5 ng/ml and not more than 300 ng/ml in said canine's blood for at least 365 days. Still more preferably, administration maintains a concentration of spinosyn of at least 10 ng/ml and not more than 225 ng/ml in said canine's blood for at least 365 days. Still more preferably, administration maintains a concentration of spinosyn of at least 25 ng/ml and not more than 200 ng/ml in said canine's blood for at least 365 days.
The following examples illustrate the methods of this disclosure:
Efficacy of Spinosyn Administered Per Os, i.e. by Mouth, to Dogs for the Treatment and Control of Ctenocephalides felis.
Methods: A pool of 40 dogs are to be preliminarily infested with ˜100 unfed adult C. felis in order to produce a pool of dogs that can suitably sustain a reliable infestation rate of approximately 50% of live fleas over a 48-hour period. The dogs with the highest live flea counts are to be randomly allocated to 4 treatment groups (6 dogs per group) based on their pre-treatment flea counts from experimental infestations. The first treatment group is to be the control group and groups 2-4 are to be the test groups.
The dogs are to be housed individually during the study period and are to be fed a commercial dry dog food ration with ad libitum access to water.
Each dog in test groups 2-4 is to receive by mouth a liquid formulation of spinosyn, preferably spinosad. The dosage is to be administered to the dogs on each of days 0-29 according to the test groups listed in TABLE 1.
Dogs in the control group are not to receive a spinosyn or any other flea control treatment. Each dog in test groups 2-4 is to be offered its daily ration (dry food) and the individual doses of liquid formulation are to be administered after the individual dog has eaten at least 25% of its total daily ration. After receiving the dose of a spinosyn the dogs are to be allowed to continue eating. This mimics incorporating the spinosyn in feed. Each dog in test groups 2-4 and the control group is to be experimentally infested with 100 unfed adult fleas on test days −1, 5, 12, 19, 28 and 35. Comb counts for live adult fleas are to be conducted on days 2, 7, 14, 21, 30 and 37. The final experimental infestation is to occur five days after the last daily dose of spinosyn.
Results: Referring now to
Using the same study method as described above, blood is to be drawn at 72, 120, 168, 336, 504, 720 and 888 hours after the initial dose of spinosyn is administered. The average concentration of spinosyn in the blood for different dosage levels can then be determined.
Sample results of the average plasma concentration of spinosad in a canine's blood at the different dosage levels are shown in TABLE 2, and
Referring now to
Efficacy of Spinosyn in Dogs when Administered in a Medicated Feed Dosed at 0.5 mg/kg of the Dog's Weight.
Methods: A pool of dogs are to be preliminarily infested with ˜100 unfed adult C. felis in order to produce a pool of 18 dogs that can suitably sustain a reliable infestation rate of approximately 50% of live fleas over a 48-hour period. The dogs with the highest live flea counts are to be randomly allocated to 3 groups (6 dogs per group) based on their pre-treatment flea counts from experimental infestations. The first treatment group is to be the control group and groups 2-3 are to be the test groups.
The dogs are to be housed individually during the study period and are to have ad libitum access to water.
There is to be an initial acclimation period of at least 4 days during which dogs in test groups 2 and 3 are to be transitioned from a standard certified commercial chow to an unmedicated version of the daily feed. During the acclimation period, the dogs are to be allowed 1 hour to consume the feed, after which the dogs' acceptance of the feed will be observed and recorded.
Each dog in test groups 2 and 3 is to receive by mouth a daily feed formulation that includes spinosyn, preferably spinosad. The dosage and formulation to be administered to the dogs on each of days 0-29 according to test groups is shown in TABLE 3.
Dogs in the control group are not to receive a spinosyn or any other flea control treatment. On days 0-29, each dog in test groups 2 and 3 is to be offered its daily feed containing spinosyn for a period of 1 hour. On days 30-37 all dogs will be given regular dog food, without spinosyn, or a physiologically acceptable derivative thereof.
Each dog in test groups 2 and 3 and the control group is to be experimentally infested with 100 unfed adult fleas on test days −1, 5, 12, 28 and 35. Comb counts for live adult fleas are to be conducted on days 2, 7, 14, 30 and 37.
Results: In a sample study using feed containing spinosad, all dogs in Groups 2 and 3 consumed all of the food required for a 0.5 mg/kg dose without regurgitating and within the 1-hour time period. Referring now to
It can be appreciated by comparing the two examples that an effective amount of a spinosyn on average can be administered to a dog via medicated feed.
While this invention has been described as having an exemplary design, the present invention may be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.
| Number | Date | Country | Kind |
|---|---|---|---|
| 63159622 | Mar 2021 | US | national |
This application is a continuation of International Patent Application No. PCT/US2022/019866, filed Mar. 11, 2022, which claims priority to U.S. Provisional Patent Application No. 63/159,622, filed Mar. 11, 2021, both of which are hereby incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63159622 | Mar 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2022/019866 | Mar 2022 | US |
| Child | 18464082 | US |
