EP1748930A2 - Pipette/applicator - Google Patents
Pipette/applicatorInfo
- Publication number
- EP1748930A2 EP1748930A2 EP05731101A EP05731101A EP1748930A2 EP 1748930 A2 EP1748930 A2 EP 1748930A2 EP 05731101 A EP05731101 A EP 05731101A EP 05731101 A EP05731101 A EP 05731101A EP 1748930 A2 EP1748930 A2 EP 1748930A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- liquid
- applicator
- shaft
- opening mechanism
- reservoir
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
- B65D1/09—Ampoules
- B65D1/095—Ampoules made of flexible material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M35/00—Devices for applying media, e.g. remedies, on the human body
- A61M35/003—Portable hand-held applicators having means for dispensing or spreading integral media
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
- B65D1/02—Bottles or similar containers with necks or like restricted apertures, designed for pouring contents
- B65D1/0223—Bottles or similar containers with necks or like restricted apertures, designed for pouring contents characterised by shape
- B65D1/023—Neck construction
- B65D1/0238—Integral frangible closures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D47/00—Closures with filling and discharging, or with discharging, devices
- B65D47/04—Closures with discharging devices other than pumps
- B65D47/06—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages
- B65D47/10—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages having frangible closures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D51/00—Closures not otherwise provided for
- B65D51/18—Arrangements of closures with protective outer cap-like covers or of two or more co-operating closures
- B65D51/20—Caps, lids, or covers co-operating with an inner closure arranged to be opened by piercing, cutting, or tearing
- B65D51/22—Caps, lids, or covers co-operating with an inner closure arranged to be opened by piercing, cutting, or tearing having means for piercing, cutting, or tearing the inner closure
- B65D51/221—Caps, lids, or covers co-operating with an inner closure arranged to be opened by piercing, cutting, or tearing having means for piercing, cutting, or tearing the inner closure a major part of the inner closure being left inside the container after the opening
- B65D51/222—Caps, lids, or covers co-operating with an inner closure arranged to be opened by piercing, cutting, or tearing having means for piercing, cutting, or tearing the inner closure a major part of the inner closure being left inside the container after the opening the piercing or cutting means being integral with, or fixedly attached to, the outer closure
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2251/00—Details relating to container closures
- B65D2251/0003—Two or more closures
- B65D2251/0006—Upper closure
- B65D2251/0015—Upper closure of the 41-type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2251/00—Details relating to container closures
- B65D2251/0003—Two or more closures
- B65D2251/0068—Lower closure
- B65D2251/0093—Membrane
- B65D2251/0096—Membrane integral with the container
Definitions
- Patent law e.g., they allow for the inclusion of additional ingredients or steps that do not detract from the novel or basic characteristics of the invention, i.e., they exclude additional unrecited ingredients or steps that detract from novel or basic characteristics of the invention, and they exclude ingredients or steps of the prior art, such as documents in the art that are cited herein o r a re incorporated by r eference h erein, e specially as it i s a g oal of this document t o define embodiments that are patentable, e.g., novel, nonobvious, inventive, over the prior art, e.g., over documents cited herein or incorporated by reference herein.
- the present invention is directed to a new and useful apparatus for dispensing 1 iquid agents. Specifically, the present invention is directed to an apparatus for applying liquids to the skin of an animal for the prevention and treatment of disease or parasite infestation.
- a syringe includes a body in which the liquid is stored, a plunger that forces the liquid out of the body, and a needle or applicator tip for accurately locating the point of application of the liquid. While such a device is well suited for injection of liquids into the body, it is not well suited for topical application.
- One obvious drawback of this device in the topical application situation is the apparent danger of puncturing the skin of the animal or the person applying the liquid when using a syringe with a needle.
- a storage chamber 52 formed of a flexible plastic material 56 and a semi or substantially rigid material 54.
- the device further comprises, a narcowed neck 58, and a break away tip 60.
- Flexible materials typically have a thickness below about lOO ⁇ m and include for example polyesters, polyamides, polypropylenes, polyolefms, and aluminum foils.
- the aluminium foils Preferably, the aluminium foils have a thickness of less than about 20 ⁇ m.
- Rigid materials typically have a thickness of below about 200 ⁇ m and include for example, polyethylene terephthalate (PET), amorphous polyethylene terephthalate (APET), polyethylene terephthalate glycol (PETG), or crystalline polyethylene terephthalate (CPET), polyvinyl chloride (PVC), polypropylene (PP), cycloolefin copolymers such as that known under the tradename COC®, poly acrilo nitrile (PAN) such as that known under the tradename BAREX®, fluropolymer or chlorotrifluoroetheylene (CTFE) such as that known under the tradename ACLAR®, and aluminum foils up to about lOO ⁇ m.
- PET polyethylene terephthalate
- APET amorphous polyethylene terephthalate
- PETG polyethylene terephthalate glycol
- CPET crystalline polyethylene terephthalate
- PVC polyvinyl chloride
- PP polypropy
- the tip 60 of the pipette 50 is broken off to allow for the free flow of the liquid agent from the storage chamber 52 to the skin of the animal via the neck 58.
- the pipette 50 is ananged on the animal so that the neck 58 of the pipette parts the animals hair, and the storage chamber 52 is squeezed to compress the flexible material 56 against the rigid material 54 and force the liquid agent through the neck 58, and onto the skin of the animal.
- This device has several drawbacks. The first of these is that the break away tip 60 can be difficult to break due to the use of the rigid materials discussed above. A struggle with the tip, by the user, can sometimes result in the undesirable release of the liquid agent onto the user.
- a liquid agent applicator that can be opened by a user single-handedly, does not have a likelihood of splashing the user with the liquid agent, and does not produce a sharp edge upon opening. It is yet another advantageous embodiment of the present invention to produce a liquid agent applicator that can be placed in an upright position after opening. It is yet another advantageous embodiment of the present invention to produce a liquid agent applicator that is child resistant. Accordingly, a liquid agent applicator is described having a collapsible reservoir for storing the liquid agent and a shaft having a lumen there through connected to the collapsible reservoir.
- the liquid agent applicator includes an opening mechanism inserted into an orifice formed in one end of the shaft and a breakable seal formed between the opening mechanism and the shaft. Further, twisting of the opening mechanism relative to the shaft breaks the seal allowing egress of the liquid agent stored in the reservoir.
- the liquid applicator includes a child resistant opening mechanism.
- the child resistant opening mechanism includes a rigid stationary neck and a movable cap.
- the child resistant opening mechanism also includes a septum for preventing the egress of liquid from the reservoir formed on the stationary neck, and a punch formed on the movable cap, for piercing the septum to allow the egress of liquid from the reservoir.
- the child resistant opening mechanism also includes an interlock requiring two or more movements of the movable cap by the user, wherein upon completion of the two or more actions, the movable cap is movable along the stationary neck in the direction of the septum. And movement of the stationary cover in the direction of the septum causes the punch to pierce the septum and release the liquid agent.
- Fig. 1 is a perspective view of a liquid applicator according to the present invention
- Fig. 2a is a front view of a prior art pipette
- Fig. 2b is a side view of a prior art pipette
- Fig. 3 a is a cross-sectional view of a shaft of a pipette according to one embodiment of the present invention
- Fig. 3b is a cross sectional view of a shaft of a pipette according to another embodiment of the present invention.
- Fig. 4 is a cross-sectional view of a CR shaft according to one embodiment of the present invention
- Fig. 5 is side view of a CR shaft according to one embodiment of the present invention.
- Fig. 1 is a perspective view of a liquid applicator according to the present invention
- Fig. 2a is a front view of a prior art pipette
- Fig. 2b is a side view of a prior art pipette
- FIG. 6 is a perspective view of a liquid applicator with a CR shaft.
- Fig. 7 is a perspective view of three examples of one embodiment of the present invention as formed by a thermoforming process.
- Fig. 8 is a front view of three examples of one embodiment of the present invention as formed by a thermoforming process.
- the pipette 10 includes a base or reservoir 12, connected to a shaft 14, and an opening mechanism 16.
- the shaft 14 has a lumen 24 extending there through fluidly connected to the reservoir 12.
- the pipette 10 is designed for easy, no-mess, one-handed use.
- the base or reservoir 12 is advantageously formed with finger grips or notches 18 formed therein to assist the user in grasping the pipette 10. These grips 18 allow the pipette to be held by the user with only two fingers, and further enable the user to apply pressure to the reservoir 12, of the pipette 10, for application of the liquid stored therein using just these two fingers.
- the grips 18 assist the user by providing means for safe and effective one handed holding and use of the pipette 10.
- the reservoir 12 is advantageously shaped with a substantially flat or slightly concave bottom 20, which enables the pipette 10 to be placed in an upright position on a flat surface such as a table or counter.
- the bottom 20 represents a considerable advantage to the user in that he/she can open the pipette 10 and place it down without fear that the contents of the pipette will spill out. Particularly in use with animals and more particularly in the application of anti-flea and tick liquids such a feature is particularly useful. Often after opening a pipette there may be reason for the pipette to be place down on a table or counter.
- the reservoir 12 is formed of a collapsible material that allows the user to apply pressure to the finger grips with just two fingers of one hand and force the fluid contained in the reservoir through the shaft 14.
- the reservoir 12 is fonned of a material having sufficient rigidity that initial grasping of the reservoir 12 by the user will not compress the reservoir 12 sufficiently to cause the liquid agent to be expelled from the orifice of the shaft 14.
- suitable plastic materials may be used to form the pipette 10. Further these plastic materials may be formed as a single or monolayer, alternatively the plastic materials may be formed as a lamination of multiple plastic layers without departing from the scope of the present invention.
- the opening mechanism 16 is formed so that twisting will remove it from the shaft 14.
- the opening mechanism 16 may be threaded like a bolt into the lumen 24 of the shaft 14.
- threads are formed on both the interior of the shaft, and the exterior of a plug 30 of the opening mechanism 16.
- the plug 30 may simply be inserted into the orifice formed at the end of the lumen 24 in the shaft 14 with sufficient force to prevent express of the fluid without removal of the plug. Twisting of the opening mechanism 16 allows the user to extract the plug 30 from the lumen 24.
- a plastic seal 25 can be formed between the plug 30 and the shaft 14, preventing the egress of liquid out of the pipette 10.
- the seal 25 may be formed, for example, of a nanowed thickness of plastic material.
- the plastic material of the seal 25 may be formed so that twisting of the opening mechanism 16 will overcome the tensile strength of the material causing it to shear, thereby breaking the seal.
- the plug 30 can be removed from the shaft 14 and an orifice is created in the shaft 14, which allows for dispensation of the fluid agent from the pipette 10.
- the seal 25 is formed of the same plastic material as the plug 30 and the shaft 14.
- opening mechanism 16 is grasped by as few as two of the user's fingers, while the pipette 10 rests in the palm of the user's hand.
- the pipette 10 is o ened one- handed. Enabling one-handed opening of the pipette simplifies the application of fluids such as flea and tick repellants to dogs and cats.
- O ne p roblem w ith pipettes cunently used in such applications, as shown in Fig. 2 is that they typically require two hands to open. This in turn may require a second person to assist in holding the animal while the user opens the pipette.
- a user may attempt to hold the animal between their knees while opening the pipette. Particularly with the very large and very small animals this can present dangers to both the animal and the user. Accordingly, by providing a pipette 10 that can be opened with a single hand, the user's second hand is free to hold the animal for application, eliminating the need for a second person and removing many of the dangers to both animal and user that other means of restraint can pose.
- Another advantage of the twist top opening mechanism 16 is that it prevents the formation of a sharp edge at the tip 22 of the shaft 14. As discussed above, use of many of the prior art devices resulted in the formation of a sharp plastic edge that could injure the animal during application.
- the sealing of the shaft 14 of the pipette 10 to the plug 30 is accomplished using the plastic materials of the plug 30 and the shaft 14 to form a seal.
- the seal has a reduced tensile strength in comparison to the plug 30 and the shaft 14 that can be sheared when the opening mechanism 16 is twisted.
- the seal may be formed in the lumen 24.
- the placement of the seal at the tip 22 of the shaft 14 may not necessarily result in the prevention of a sharp edge forming on the tip 22 upon the removal of the opening mechanism 16 from the shaft 14. Accordingly, by forming the seal between the shaft 14 and the plug 30 of the opening mechanism 16 inside the lumen 24, no sharp edge will be fonned on the tip 22. As a result the dangers associated with such a sharp edge are greatly reduced and there is little likelihood of injury to either the user or the animal.
- the shaft 14 of the pipette 10 is advantageously formed of a substantially rigid material that resists bending.
- the shaft 14 is also formed with a long neck to assist in proper dosing.
- the long neck and resistance to bending provide beneficial support for the pipette 10 during application of the fluid agent on the animal.
- the stiffness or resistance to bending and the long neck allow the user to easily part the animal's hair or fur for application directly on the animals skin.
- the shaft 14 is between 1 and 5cm in length.
- the break away tip 60 as shown in Fig. 2 a and b, tends to remain connected to the pipette which further frustrates proper dosing. In certain circumstances this could result in the animal receiving insufficient treatment and thereby compromise the effectiveness of the treatment regimen. Accordingly, the present invention provides for superior application and greater guarantees of proper dosing of the animal.
- Another embodiment of the present invention is a child resistant or CR shaft 44, for use with the pipette 10.
- the CR shaft 44 includes a rigid stationary neck 45, a movable cap 48, and a septum 46.
- the septum 46 acts as a seal on the pipette 10 preventing the egress of a liquid agent contained therein.
- the movable cap 48 includes a punch 49.
- the punch 49 includes a piercing tip of sufficient rigidity to allow the punch 49 to pierce the septum 46.
- the piercing of the septum 46 allows for the free flow of the liquid agent from the reservoir 12 of the pipette 10 to the CR shaft 44. After piercing of the septum 46, the cap 48 is removed and the liquid is able to flow from the pipette 10.
- the CR shaft 44 also includes a means for preventing a child from opening the pipette 10. This means for preventing a child from opening the pipette 10 may be of a type know in the art.
- the prevention means can include requiring depression or extension of the movable cap 48 vertically to a first position and twisting of the cover while in this first position to a rotational stop point.
- the cap 48 may include a lumen (not shown) which extends through the punch 49. This allows for egress of fluid from the pipette 10 after piercing of the septum 46.
- One method of manufacturing such a pipette 10 is called thermoforming.
- thermoforming process sheets of a desired plastic material are fed into a press. These sheets may be formed of one or more layers of plastic material.
- the press contains a mold of the shape to be formed for example, the reservoir 12 of the pipette 10.
- the air pressure forces a portion of the now heated plastic sheets into the molds to form the shape of the reservoir 12.
- the heat acts to seal the two sheets of plastic material together to form a single plastic sheet having a reservoir 12. The heat is removed, and upon cooling, reservoir 12 may be cut from the plastic sheet.
- Figs. 7 and 8 show three examples of the present invention formed by a thermoforming process.
- the reservoir 12 can then be filled with the desired liquid agent, for example a flea and tick repellant for use with domestic animals such as dogs and cats.
- the shaft 14 with opening mechanism 16 is inserted into an opening in the reservoir 12. Further application of heat to the opening in the reservoir 12 acts to seal the reservoir 12 to the shaft 14, thereby creating a sealed pipette 10 which can then be cut from the sheet of plastic for packaging and sale.
- the base 12 is formed and the shaftl4 inserted therein. After application of heat to the b ase 12 a nd s haft 14 c ombination, the 1 iquid a gent i s added via an orifice in the end of the shaftl4. After filling the opening mechanism 16 is inserted into the orifice. Application of yet another source of heat seals the opening mechanism 16 to the shaft
- liquid agent may be stored and administered to the animal or human by this applicator.
- Prefened liquid agents are topical pharmaceutical or veterinary formulations.
- Therapeutic agents, which are present in the fonnulations include, for example, substances or combination of substance such as, for example, antiviral, antibacterial, antiparasitic, antifungal substances and combinations thereof.
- the therapeutic agent may further be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.
- Anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone and the like.
- Anti-bacterial agents such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracyclines, chloramphenicol, erythromycin, streptomycin, and the like.
- Antiparasitic agents such as quinacrine, chloroquine, quinine, and the like.
- Antifungal agents such as nystatin, gentamicin, miconazole, tolnaftate, undecyclic acid and its salts, and the like.
- Antiviral agents such as vidarabine, acyclovir, ribarivin, amantadine hydrochloride, iododeoxyuridine, dideoxyuridine, interferons and the like.
- Antineoplastic agents such as methotrexate, 5-fluorouracil, bleomycin, tumor necrosis factor, tumor specific antibodies conjugated to toxins, and the like.
- Analgesic agents such as salicylic acid, salicylate esters and salts, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmetin, zomepirac, and the like.
- Local anaesthetics such as cocaine, benzocaine, novocaine, lidocaine, and the like.
- Vaccines, or antigens, epitopes, immunogens of human or animal pathogens such as hepatitis, influenza, measles, mumps, rubella, hemophilus, diphtheria, tetanus, rabies, polio, as well as veterinary vaccines and the like.
- Central nervous system agents such as tranquilizers, sedatives, anti-depressants, hypnotics, ⁇ -adrenergic blocking agents, dopamine, and the like.
- Growth factors such as colony stimulating factor, epidermal growth factor, erythropoietin, fibroblast growth factor, neural growth factor, human growth hormone, platelet derived growth factor, insulin-like growth factor, and the like.
- Hormones such as progesterone, estrogen, testosterone, follicle stimulating hormone, chorionic gonadotrophin, insulin, endorphms, somatotropins and the like.
- Antihistamines such as diphenhydramine, chlorpheneramine, chlorcyclizine, promethazine, cimetidine, terfenadine, and the like.
- Cardiovascular agents such as verapamil hydrochloride, digitalis, streptokinase, nitroglycerine paparefine, disopyramide phosphate, isosorbide dinitrate, and the like.
- Anti-ulcer agents such as cimetidine hydrochloride, sopropamide iodide, propantheline bromide, and the like.
- Bronchodilators such as metaproternal sulfate, aminophylline, albuterol, and the like.
- Vasodilators such as theophylline, niacin, nicotinate esters, amylnitrate, minoxidil, diazoxide, nifedipine, and the like.
- the therapeutic agents which are used in the formulations for the inventive applicator can be well known to the practitioner to which this invention pertains.
- Classes of therapeutic agents contemplated by the inventive formulations include insecticides, acaricides, parasiticides, growth enhancers, and oil-soluble, nonsteroidal anti-inflammatory drugs (NSAIDs).
- Specific classes of compounds which fall within these classes include, for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazoles, and COX-2 inhibitors.
- the avermectin and milbemycin series of compounds are potent anthelmintic and antiparasitic a gents against a wide range of internal and external parasites.
- the compounds which belong to this series are either natural products or are semi-synthetic derivatives thereof.
- the structure of these two series of compounds are closely related and they both share a complex 16-membered macrocyclic lactone ring; however, the milbemycin do not contain the aglycone substitutent in the 13 -position of the lactone ring.
- the natural product avermectms are disclosed in U.S.
- Patent 4,310,519 to Albers-Schonberg, et al, and the 22, 23-dihydro avermectin compounds are disclosed in Chabala, et al, U.S. Patent 4,199,569.
- avermectins which include a discussion of their uses in humans and animals, see "Ivermectin and Abamectin," W.C. Campbell, ed., Springer- Verlag, New York (1989).
- bioactive agents such as avermectins or ivermectin can be used in combination with other bioactive agents; and, with respect to avermectins, ivermectin, and bioactive agent combinations, reference is made to Kitano, U.S. Patent No. 4,468,390, Beuvry et al., U.S. Patent No. 5,824,653, von Bittera et al., U.S. Patent No. 4,283,400, European Patent Application 0 007 812 Al, published June 2, 1980, U.K. Patent Specification 1 390 336, published April 9, 1975, European Patent Application 0 002 916 A2, Ancare New Zealand Patent No.
- Nodulisporic acid and its derivatives are a class of acaricidal, antiparasitic, insecticidal and anthelminitic agents known to a practitioner of the art. These compounds are used to treat or prevent infections in humans and animals. These compounds are described, for example, in U.S. Patent 5,399,582 and WO 96/29073.
- Especially prefened therapeutic agents include nodulisporic acid compounds A, B, and C as well as nodulisporic acid derivatives of the formula:
- Rf is (1) hydrogen, (2) optionally substituted alkyl, (3) optionally substituted alkenyl, (4) optionally substituted alkynyl, (5) optionally substituted cycloalkyl, (6) optionally substituted cycloalkenyl, where the substituents on the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from (i) alkyl, (ii) alkyl, where X is O or S(O) m .
- Y 1 and Y 2 are independently H or alkyl, (ix) alkanoylamino, and (x) aroylamino wherein said aroyl is optionally substituted with 1 to 3 groups independently selected from R • (7) aryl or arylalkyl, wherein said aryl is optionally substituted with 1 to 3 groups independently selected from R , (8) perfluoroalkyl (9) a 5- or 6-member heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms optionally substituted by 1 to 3 groups independently selected from hydroxy, oxo, alkyl and halogen, and which may be saturated or partly unsaturated,
- R 2 , R 3 , and P ⁇ t are independently OR a , OC0 2 R b , OC(O)NR c R d ; or
- R 7 is (1) CHO, or (2) the fragment R 8 is (1) H, (2) OR a , or (3) NR c R d
- R 9 is (1) H, or (2) OR a ; Rio is (1) CN,
- R a is (1) hydrogen
- R b is (1) H, (2) optionally substituted aryl, (3) optionally substituted alkyl, (4) optionally substituted alkenyl, (5) optionally substituted alkynyl, (6) optionally substituted cycloalkyl, (7) optionally substituted cycloalkenyl, or (8) optionally substituted heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen; where the substituents on the aryl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groups independently selected from (i) hydroxy, (ii) alkyl, (iii) oxo, (iv) SO 2 NR g R h , (v) arylalkoxy, (vi) hydroxyalkyl, (vii) alkoxy, (viii) hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano, (xi) mercapto,
- R c and R d together with the N to which they are attached form a 3- to 10-member ring containing 0 to 2 additional heteroatoms selected from O, S(O) m , and N, optionally substituted with 1 to 3 groups independently selected from R g , hydroxy, thioxo and oxo;
- R e is (1) halogen, (2) alkyl, (3) perfluoroalkyl, (4) -SCOJmR 1 , (5) cyano, (6) nitro, (7) R ⁇ o(CH 2 )v-, (8) RCOz CHz , (9) R i OCO(CH 2 )v-, (10) optionally substituted aryl where the substituents are from 1 to 3 of halogen, alkyl, alkoxy, or hydroxy, (11) SO 2 NR g R h , or (12) amino;
- R f is (1) alkyl, (2) X-C1-C alkyl, where X is O or S(O) m , (3) alkenyl, (4) alkynyl, (5) perfluoroalkyl, (6) N ⁇ 'Y 2 , where Y 1 and Y 2 are independently H or alkyl, (7) hydroxy, (8) halogen, and (9) alkanoylamino,
- R g and R h are independently (1) hydrogen, (2) alkyl optionally substituted with hydroxy, amino, or CO 2 R " (3) aryl optionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkyl or perfluoroalkyl, (4) arylalkyl, wherein the aryl is optionally substituted with perfluorolkyl or 1 ,2-methylenedioxy; (5) alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) aryl alkoxycarbonyl, (10) aminocarbonyl, (11) monoalkylaminocarbonyl (12) dialkylaminocarbonyl; or R g and R h together with the N to which they are attached form a 3- to 7-member ring containing 0 to 2 additional heteroatoms selected from O, S(O) m , and N, optionally substituted with 1 to 3 groups independently selected from R e and oxo; R 1 is (1) hydrogen, (2) per
- R x is selected from the group consisting of: H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH(CO 2 CH 3 )CH 2 OH, CH 2 CO 2 CH 3 ,
- a prefened class of compounds of formula (I) comprises the compounds such that Ri is
- R 3 is haloalkyl
- Rj is NH 2
- Rn and R ⁇ 2 are, independently of one another, a halogen atom
- R 13 is haloalkyl.
- X is C-Ri 2 -
- a compound of formula (I) which is very particularly prefened in the invention is 5-amino-3 -cyano- l-(2,6-dichloro-4- trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole or fipronil.
- IGR Insect growth regulating
- French Patent No. A-2,713,889 generally describes an IGR combination comprising at least one compound with juvenile hormone activity and chitin synthesis inliibitors, with at least one of three N-arylpyrazole compounds, in particular fipronil or thiofipronil, to control many harmful insects belonging to very varied orders.
- IGR compounds which may be used in this invention include compounds which mimic juvenile hormones, in particular: azadirchtin - Agridyne diofenolan (Ciba Geigy now Novartis) fenoxycarb (Ciba Geigy now Novartis) hydroprene (Sandoz now Novartis) kinoprene (Sandoz now Novartis) methoprene (Sandoz now Novartis) pyriproxyfen (Sumitomo/Mgk) tetrahydroazadirachtin (Agridyne) 4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3- pyridylmethoxy)pyridizin-3 (2H)-one and chitin-synthesis inhibitors, in particular: chlorfluazuron (Ishihara Sangyo) cyromazine (Ciba Geigy now Novartis)
- Chitin-synthesis inhibitors also include compounds such as l-(2,6-difluorobenzoyl)-3-(2- fluoro-4-((trifluoromethyl)) phenylurea, 1 -(2,6-difluorobenzoyl)-3 -(2-fluoro-4-(l , 1 ,2,2- tetrafluoroethoxy))phenylurea and 1 -(2,6-difluorobenzoyl)-3 -(2-fluoro-4-trifluoro- methyl)phenylurea.
- Novaluron (Isagro, Italian company) is also an example of an IGR compound.
- Prefened IGR compounds include methoprenes, pyriproxyfens, hydroprene, cyromazine, lufenuron, l-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea and novaluron.
- Estrogens, progestins, and androgens refers to classes of chemical compounds which are also well known to a practitioner in this art. In fact, estrogens and progestins are among the most widely prescribed drugs and are used, for example, alone or in combination for contraception or hormone replacement therapy in post menopausal women.
- Estrogens and progestins occur naturally or are prepared synthetically. This class of compounds also includes estrogens or progesterone receptor antagonists. Antiestrogens, such as tamoxifen and clomiphene, are used to treat breast cancer and infertility. Antiprogestives are used as contraceptives and anticancer drugs, as well as to induce labor or terminate a pregnancy. The androgens and antiandrogens structurally related to the estrogens and progestins as they are also biosynthesized from cholesterol. These compounds are based on testosterone. Androgens are used for hypogonadism and promote muscle development.
- Antiandrogens are used, for example, in the management of hyperplasia and carcinoma of the prostate, acne, and male pattern baldness as well as in the inhibition of the sex drive in men who are sex offenders.
- Estrogen, progestins, and androgens are described, for example, in "Goodman & Gilman's The Pharmacological Basis of Therapeutics," 9 th ed., J.G. Handman and L. Elimbird, eds., Ch. 57 to 60, pp. 1411-1485, McGraw Hill, New York (1996) or in "Principles of Medicinal Chemistry," 2 nd ed., W.O. Foye, ed., Ch. 21, pp.
- Estrogens, progestins and androgens are also used in animal husbandry as growth promoters for food animals. It is known in the art that compounds of these classes act as growth-promoting steroids in animals such as cattle, sheep, pigs, fowl, rabbits, etc. Delivery systems to promote the growth of animals are described, for example, in U.S. Patent 5,401,507, U.S. Patent 5,288,469, U.S. Patent 4,758,435, U.S. Patent 4,686,092, U.S. Patent 5,072,716 and U.S. Patent 5,419,910. NSAIDs are well known in the art.
- the classes of compounds which belong to this group include salicylic acid derivatives, para-aminophenol derivatives, indole and indene acetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids (fenamates), enolic acids, and alkanones.
- NSAIDs exert their activity by interfering with prostaglandin biosynthesis by hreversibly or reversibly inhibiting cycloxygenase.
- COX-2 inhibitors which act by inhibiting the COX-2 receptor.
- Compounds of this group possess analgesic, antipyretic and nonsteroidal anti-inflammatory properties.
- Especially prefened COX-2 inhibitors include 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one or 3-(cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one, including the polymorphic B form of this compound, and the pharmaceutically acceptable salts or hydrates of these compounds.
- Macrohdes are a class of antibiotics which contain a many-membered lactone ring to which are attached one or more deoxy sugars. Macrohdes are generally bacteriostatic, but have been shown to be bacteriocidal in high concentration against very susceptible organisms. Macrohdes are most effective against gram-position cocci and bacilli, although they do possess some activity against some gram-negative organism. Macrohdes exert their bacteriostatic activity by inhibiting bacterial protein synthesis by binding reversibly to the 50 S ribosomal subunit. ("Goodman & Gillman's the Pharmacological Basis of Therapeutics," 9th ed., J.G. Hadman & L.E. Limbird, eds., ch. 47, pp.
- the macrohdes as a class are colorless and usually crystalline.
- the compounds are generally stable in near neutral solution, but they only have limited stability in acid or base solutions. The reason for this is because the glycosidic bonds hydrolyze in acid and the lactone ring saponifies in base ("Principles of Medicinal Chemistry," 2nd ed., W.F. Foye, ed., ch. 31, pp. 782-785, Lea & Febiger, Philadelphia (1981)).
- the macrolide anthelmintic compounds contemplated for use in the present invention are also well known to a practitioner of this art. These compounds include avermectins and milbemycins discussed above. Non-limiting examples of compounds belonging to this class are represented by the following structure:
- Ri is hydrogen or hydroxy provided that Ri is present only when the broken line indicates a single bond
- R 2 is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms or cycloalkyl of from 3 to 8 carbon atoms
- R 4 is hydrogen, hydroxy or
- e is hydroxy, amino, mono-or di-lower alkylamino or lower alkanoylamino.
- Additional compounds are avermectin Bla/Blb (abamectin), 22,23-dihydro avermectin
- Bla/Blb ivermectin
- 4"-acetylamino-5-ketoximino derivative of avermectin Bla/Blb Both abamectin and ivermectin are approved as broad-spectrum antiparasitic agents.
- the 4"- acetyl amino-5-ketoximino derivatives of avermectin Bla/Blb has the following structural formula:
- R 2 is isopropyl or sec-butyl.
- the avermectin products are generally prepared as a mixture of at least 80% of the compound where R 2 is sec-butyl and no more than 20% of the compound where 2 is isopropyl.
- Other known avermectins include ememectin, eprinomectin and doramectin.
- Prefened milbemycin compounds which may be used as therapeutic agents include milbemycin ⁇ i and moxidectin.
- the monosaccharide avermectin derivatives are also useful in combination with the present invention, especially where an oxime substitution is present on the 5-position of the lactone ring. Such compounds are described, for example, in EP 667,054.
- the bioactive agent in the present invention can be a macrolide, as macrohdes are soluble in many organic solvents but are only slightly water soluble. Macrohdes as a class include the erythromycin and its derivatives as well as other derivatives such as the azalides. Erythromycin (MW 733.94 daltons) is the common name for a macrolide antibiotic produced by the growth of a strain of Streptomyces erythreous.
- Erythromycin has a broad and essentially bacteriostatic action against many Gram- positive and some Gram-negative bacteria as well as other organisms including mycoplasmas, spirochetes, chlamydiae and rickettsiae. In humans, it finds usefulness in the treatment of a wide variety of infections. It finds wide application in veterinary practice in the treatment of infectious diseases such as pneumonias, mastitis, metritis, rhinitis, and bronchitis in cattle, swine and sheep.
- erythromycins include carbomycin, clarithromycin, josamycin, leucomycins, midecamycins, mikamycin, miokamycin, oleandomycin, pristmamycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, tylosin, troleandomycin, and virginiamycin.
- carbomycin is a mixture of carbomycin A and carbomycin B.
- Leucomycin exists as a mixture of components A l9 A 2 , A 3 , A , B ⁇ -B 4 , U and V in various proportions.
- Component A 3 is also known as josamycin and leucomycin V is also known as miokomycin.
- T he major components of the midecamycins is midecamycin A and the minor components are midecamycins A 2 , A 3 and A 4 .
- mikamycin is a mixture of several components, mikamycin A and B.
- Mikamycin A is also known as virginiamycin Mi.
- Pristinamycin is composed of pristinamycins IA, IB, and Ic, which are identical to virginiamycins B 2 , B ⁇ 3 and B 2 respectively, and pristinamycin H A and Il ⁇ , which are identical to virginiamycin Mi and 26,27-dihydrovirginiamycin Mi.
- Spiramycin consists of three components, spiromycin I, II, and III. Virginiamycin is composed of virginiamycin Si and virginiamycin M ⁇ . All these components may be used in this invention. Sources of these macrohdes are well known to the practitioner and are described in the literature in references such as "The Merck Index," 12th ed., S. Budarari, ed., Merck & Co., Inc., Whitehouse Station, NJ (1996).
- the azalides are semisynthetic macrolide antibiotics related to erythromycin A and exhibit similar solubility characteristics. The structure of azithromycin is known. Useful azalide compounds are disclosed in EP 508699, herein incorporated by reference.
- the conesponding basic and acid addition salts and ester derivatives of the macrohdes compounds are also contemplated for use in this invention. These salts are formed from the conesponding organic or inorganic acids or bases. These derivatives include the customary hydrochloride and phosphate salts as well as the acetate, propionate and butyrate esters. These derivatives may have different names. For example, the phosphate salt of oleandomycin is matromycin and the triacetyl derivative is troleandomycin. Rokitamycin is leucomycin V 4-B-butanoate, 3B- propionate. Combinations of one or more of the therapeutic agents described above are contemplated.
- the therapeutic agents nodulisporamide derivatives or 1-N- arylpyrazoles may be combined with other insecticides, parasiticides, and acaricides.
- Such combinations include anthelminitic agents, such as those discussed above which include ivermectin, avermectin, and emamectin, as well as other agents such as thiabendazole, praziquantel, febantel or morantel.
- other combinations may include imidicloprid or a COX-2 inhibitor.
- Non-limiting examples of topical formulations that are prefened include those comprising: a) a pharmaceutically ctive c ombination consisting of at least one macrocyclic lactone and at least one compound selected from the group consisting of praziquantel, morantel and pyrantel; b) optionally, a thickening agent; c) a non-aqueous solvent; and d) optionally, an antioxidant, a colorant, an acidifying stabilizer, an opacifier, a preservative and a crystallization inhibitor, wherein the pharmaceutically active combination is disclosed in the non- aqueous solvent.
- compositions may be of the spot-on or pour-on type.
- Other prefened spot-on and pour-on compositions include formulations comprising: (A) 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4- trifluoromethylsulfinylpyrazole; or (B) 1-N-phenylpyrazole derivative of the formula:
- prefened spot-on or pour-on formulations are those comprising, for example, comprising from 0.05 to 25 % weight/volume, relative to the total solution, of a compound of the formula:
- R 1 represents H 2 N-CS-;
- R 2 represents S(O) n R, 4,5-dicyanoimidazol-2-yl or haloalkyl;
- R 3 represents alkyl, haloalkyl, haloalkenyl or haloalkynyl;
- R 4 represents hydrogen, halogen, alkyl, haloalkyl, amino or a compound selected from the group consisting of
- R represents alkyl, halogenoalkyl, alkoxyalkyl or in each case unsubstituted or substituted phenyl or pyridyl
- R 6 represents hydrogen or alkyl
- R 7 represents hydrogen, alkyl or in each case unsubstituted or substituted phenyl or pyridyl
- prefened are those, for example, which contain Frontline®, Frontline plus®, or Revolution®, as described in U.S. Patents Nos. 6,426,333; 6,482,425; 6,395,765; 6,096,329; and 6,685,954.
- Other especially prefened spot-on or pour-on formulations include: synergistic spot-on compositions for the long lasting protection against ectoparasites on mammals which comprises synergistic amounts (A) at least one compound of the formula:
- Ri is CN or methyl or a halogen atom
- R 2 is S(O)trust R 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
- R 3 is alkyl or haloalkyl
- R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(0)alkyl, alkoxycarbonyl or S(O) r — CF 3 radical; R 5 and e may together fonn a divalent allcylene radical which may be interrupted by one or two divalent hereto atoms or;
- R 7 represents an alkyl or haloalkyl radical
- R 8 represents an alkyl or haloalkyl radical or a hydrogen atom
- R 9 represents an alkyl radical or a hydrogen atom
- Rio represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or one or more substituents selected from the group consisting of OH, — O-alkyl, S-alkyl, cyano or alkyl;
- Rn and R ⁇ 2 represent, independently of each other, hydrogen, halogen, CN orN0 2 ;
- R ⁇ 3 represents a halogen atom or a haloalkyl, haloalkoxy, S(O) g CF 3 or SF 5 group; m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2;
- a fluid vehicle comprising at least one customary spot-on formulation adjuvant; or a composition comprising (A) an effective amount of at least one compound of the formula
- Ri is a halogen atom, CN or methyl
- R 2 is S(O) friendshipR 3 or 4,5-dicyanoimidazol-2-yl or haloalkyl
- R 3 is alkyl or haloalkyl
- Rn represents a hydrogen or halogen atom or an NRsRe, (S)O) m
- R 7 represents a hydrogen or halogen atom or an NRsRe, (S)O) m
- C(O)R 7 , alkyl, haloalkyl or 0 8 radical or an -N C(R 9 )(R ⁇ o) radical
- R 5 and R 6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, S(O) r CF 3 or alkoxycarbonyl radical or R 5 and Re can together form a divalent alkylene radical which is optionally interrupted by one or two divalent heteroatoms
- R 7 represents an alkyl or
- Frontline ® is a spot-on product comprises fipronil, ethanol, polvidone, Tween 80, butylhydroxytoluene, butlyhydroxyanisole and diethylene glycol monomethylether.
- Frontline Plus® contains the same ingredients as Frontline® except that it further includes (S)- methoprene.
- Revolution® is a spot-on product comprising selamectin in isopropanol, polyvidone, Tween 80, butylhydroxytoluene, dipropylene glycol monomethylether.
- the topical formulations used in the present invention may include other formulations adjuvants well know to a practitioner in this art.
- these additives are as follows:
- the thickeners are well known to a practitioner of this art and may be added to these formulations.
- Compounds which function as thickeners include, for example, povidone, maltodextrin, polydextrate, EMDEX (dextrates), carboxypolymethylene (Carbomer®), polyethylene glycol and celluloses, such as hydroxypropyl celluloses.
- An especially prefened thickener is povidone.
- Thickeners may be present in amounts of from about 0.1% to about 25%.
- Opacifiers may be added to absorb and or reflect certain light and/or energy of certain wavelengths and may thus enhance the stability of the formulations.
- Opacifiers include, for example, zinc oxide or titanium dioxide and may be present in amounts from about 0.5 to 2.5%.
- Titanium dioxide is especially prefened. These compounds are well known to practitioners of this art. Additionally, the formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the formulation art. Antioxidant such as an alpha tocopheral, ascorbic acid, ascrobyl palmitate, fumeric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol and the like, may be added to the present formulation.
- antioxidants such as antioxidants, preservatives, or pH stabilizers.
- Antioxidant such as an alpha tocopheral, ascorbic acid, ascrobyl palmitate, fumeric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butyl
- the antioxidants are generally added to the formulation in amounts of from about 0.01 to about 2.0%, based upon total weight of the formulation, with about 0.05 to about 1.0% being especially prefened.
- Preservatives such as the parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging from about 0.01 to about 2.0%), with about 0.05 to about 1.0% being especially prefened.
- preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Prefened ranges for these compounds include from about 0.01 to about 5%.
- Colorants may be added to the formulations.
- Specific colorants include, for example, dyes, an aluminum lake, caramel, colorant based upon iron oxide or a mixture of any of the foregoing.
- organic dyes and titanium dioxide are especially useful. Prefened ranges include from about 0.1% to about 25%.
- Solvents for the formulations would be readily known in the art and include, for example, glycerol formal, 1-methylpynolidone (NMP), propylene, glycol, polyethylene glycol, benzyl alcohol, mixtures of glyceride/triglyceride and their derivatives, such as caprilic/capric acid triglyceride, or fatty acid esters (miglyol products) diethylene glycol monoethyl ether (transcutol®), lauroglycol 90, dimethylfomamide (DMF), dimethyl sulfoxide (DMSO) and mixtures of these solvents.
- NMP 1-methylpynolidone
- NMP 1-methylpynolidone
- propylene glycol
- polyethylene glycol polyethylene glycol
- benzyl alcohol mixtures of glyceride/triglyceride and their derivatives
- fatty acid esters milyol products
- diethylene glycol monoethyl ether transcutol
- Administration of the inventive formulation may be intermittent in time and may be administered daily, weekly, biweekly, monthly, bimonthly, quarterly, or even for longer durations of time.
- the time period between treatments depends upon factors such as the parasite(s) being treated, the degree of infestation, the type of mammal or bird and the environment where it resides. It is well within the skill level of the practitioner to determine a specific administration period for a particular situation.
- Spot-on and pour-on formulations may be prepared by dissolving the therapeutic agents into the pharmaceutically or veterinary acceptable vehicle.
- the spot-on formulation can be prepared by encapsulation of the active ingredient to leave a residue of the therapeutic agent on the surface of the animal.
- formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the therapeutic agent, the species of host animal to be treated, the severity and type of infection and the body weight of the host.
- the compounds may be administered continuously, particularly for prophylaxis, by known methods. Generally, a dose of from about 0.001 to about 10 mg per kg of body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but, of course, there can be instance where higher or lower dosage ranges are indicated and such are within the scope of this invention. It is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific therapeutic agent for a specific host and parasite.
- a single formulation containing for example, a 1 -N-arylpyrazole derivative in a substantially liquid carrier and in a form which makes p ossible a single application, or an application repeated a small number of times will be administered to the animal over a highly localized region of the animal, preferably between the two shoulders. Most preferably, this localized region has a surface area of less than 10 cm 2 , especially between 5 and 10 cm 2 area. It also may be preferable to use controlled-release formulations. It is understood that the dosage values which are thus indicated are average values which may vary within a wide range.
- a formulation having defined doses of 1-N- arylpyrazole-type derivative and of an IGR compound will be administered to animals having relatively different weights. Consequently, the doses actually applied are often smaller or larger by a factor which may be up to 2, 3 or 4 relative to the prefened dose, without entailing any toxic risk for the animal in the case of an overdose, and while at the same time retaining real efficacy, possibly of shorter duration, in the case of an underdose.
- the spot-on formulations that are used in present invention provide for the topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to a spot on the animal, generally between the two shoulders (solution pf spot-on type).
- inventive formulations are especially active against parasites when the formulations are applied to mammals and birds, especially poultry, dogs, cats, sheep, pigs, cattle zebras, horses, donkeys, mice, chipmunks and tree squinels.
- pharmaceutically or veterinary-acceptable acid or base salts where applicable, of the therapeutic agents provided for herein.
- the term "acid” contemplates all pharmaceutically or veterinary acceptable inorganic or organic acids.
- Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids.
- Organic acids include all pharmaceutically or veterinary-acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids.
- Prefened acids are straight chain or branched, saturated or unsaturated C ⁇ -C 2 o aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C 6 -C ⁇ 2 aromatic carboxylic acids.
- acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, ⁇ - hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid.
- dicarboxylic acids include oxalic acid, malic acid, succinic acid, tataric acid and maleic acid.
- An example of a tricarboxylic acid is citric acid.
- Fatty acids include all pharmaceutically or veterinary-acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms.
- bases contemplates all pharmaceutically or veterinary acceptable inorganic or organic bases.
- bases include, for example, the alkali metal and alkaline earth metal salts, such as the lithium, sodium, potassium, magnesium or calcium salts.
- Organic bases include the common hydrocarbyl and heterocyclic amine salts, which include, for example, the morpholine and piperidine salts.
- the organic solvent for the liquid canier vehicle will preferably have a dielectric constant of between about 10 and about 35, preferably between about 20 and about 30, the content of this solvent in the overall composition preferably representing the remainder of 100% of the composition. It is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters.
- the organic cosolvent for the liquid canier vehicle will preferably have a boiling point of less than about 100°C, preferably of less than about 80°C, and will have a dielectric constant of between about 10 and about 40, preferably between about 20 and about 30; this cosolvent can advantageously be present in the composition according to a weight/weight (W/W) ratio with respect to the solvent of between about 1/15 and about 1/2; the cosolvent is volatile in order to act in particular as drying promoter and is miscible with water and/or with the solvent. Again, it is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters.
- the organic solvent for the liquid canier includes the commonly acceptable organic solvents known in the formulation art.
- solvents may be found, for example, in Remington Pharmaceutical Science, 16 th Edition (1986). These solvents include, for example, acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, dichloromethane or diethylene glycol monoethyl ether (Transcutol). These solvents can be supplemented by various excipients according to the nature of the desired phases, such as C 8 -C ⁇ o caprylic/capric triglyceride a hydrogenated or fractionated coconut oil (Estasan or Miglyol 812), oleic acid or propylene glycol.
- the liquid canier may also comprise a microemulsion.
- Microemulsions are also well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids. Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions).
- the interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co- SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
- SA surface-active
- Co- SA co-surface-active
- the oily phase can in particular be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds.
- the oily phase preferably comprises triglycerides and more preferably medium-chain triglycerides, for example C 8 -C ⁇ o caprylic/capric triglyceride.
- the oily phase will represent, in particular, from about 2 to about 1 5% m ore, p articularly from about 7 to about 10%, preferably from about 8 to about 9%, V/V of the microemulsion.
- Suitable oils for the oily phase are known in the art and are described, for example, in U.S. Patent 6,036,394; U.S. Patent 5,580,574; U.S. Patent 6,174,540 and WO 97/37653, herein incorporated by reference.
- the aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
- Propylene glycol, diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether are especially prefened.
- the aqueous phase will represent a proportion from about 1 to about 4% V/V in the microemulsion.
- Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolysed C 8 -C ⁇ o glycerides or polyglyceryl-6 dioleate.
- the cosurfactants include short-chain alcohols, such as ethanol and propanol.
- cosurfactant to surfactant ratio will preferably be from about 1/7 to about 1/2. There will preferably be from about 25 to about 75% V/V of surfactant and from about 10 to about 55% V/V of cosurfactant in the microemulsion.
- co-solvents are also well known to a practitioner in the formulation art. Prefened co-solvents are those which are promoters of drying and include, for example, absolute ethanol, isopropanol (2-propanol) or methanol.
- the crystallization i nhibitor c an i n particular b e p resent i n a p roportion o f about 1 to about 20%) (W/V), preferably of about 5 to about 15%.
- the inhibitor preferably conesponds to the test in which 0.3 ml of a solution comprising 10% (W/V) of the compound of formula (I) in the liquid carrier and 10% of the inhibitor are deposited on a glass slide at 20°C and allowed to stand for 24 hours. The slide is then observed with the naked eye.
- Acceptable inhibitors are those whose addition provides for few or no crystals, and in particular 1 ess than 10 crystals, preferably 0 crystals.
- the formulation can optionally comprise water, in particular in a proportion of 0 to about 30% (volume by volume V/V), in particular of 0 to about 5%, although this is not always prefened.
- the formulation can also comprise an antioxidizing agent intended to inhibit oxidation in air, this agent being particularly present in a proportion of about 0.005 to about 1% (WV), preferably of about 0.01 to about 0.05%. Crystallization inhibitors which may be included in the spot-on or pour-on formulation.
- Non-limiting examples of crystallization inhibitors include: polyvinylpynolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpynolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, - anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water
- a crystallization inhibitor pair will be used.
- Such pairs include, for example, the combination of a film-forming agent of polymeric type and of a surface-active agent. These agents will be selected in particular from the compounds mentioned above as crystallization inhibitors.
- Particularly prefened film-forming agents of polymeric type include: the various grades of polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinyl acetate and of vinylpynolidone.
- Especially prefened surface-active agents include those made of non-ionic surfactants, preferably polyoxyethylenated esters of sorbitan and in particular the various grades of polysorbate, for example Polysorbate 80.
- the film-forming agent and the surface-active agent can in particular be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.
- the pair thus constituted secures, in a noteworthy way, the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the fur, that is to say without a tendency towards sticking or towards a sticky appearance, despite the high concentration of active material.
- Particularly prefened antioxidizing agents are those conventional in the art and include, for example, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate or a mixture of not more than two of them.
- composition adjuvants discussed above are well known to the practitioner in this art and may be obtained commercially or through known techniques. These concentrated compositions are generally prepared by simple mixing of the constituents as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added.
- the determination of an effective amount of a given therapeutic agent would be well known to the p ractitioner s ince many the individual agents an combinations containing these agents are known.
- the amount of 1 -N-arylpyrazole for birds and animals which are small in size is preferably greater than about 0.01 mg and in a particularly prefened way between about 1 and about 50 mg/kg of weight of animal.
- Prefened doses are from about 5 to about 15 mg/kg of 1-N-arylpyrazoles and from about 0.5 to about 15 mg/kg for the prefened IGR compounds, or about 10 to about 20 mg/kg for the other IGR compounds.
- the liquid carrier vehicle comprises a pharmaceutically or veterinary acceptable organic solvent and optionally an organic cosolvent.
- the volume applied can be of the order of about 0.3 to about 1 ml, preferably of the order of about 0.5 ml, for cats and of the order of about 0.3 to about 3 ml for dogs, depending on the weight of the animal.
- nodulisporic acid derivatives generally a dose of from about 0.001 to about 100 mg per kg of body weight, with a range of 0.25 to 50 mg/kg being especially prefened, given as a single dose or in divided doses for a period of from about 1 to about 60 days, preferably from about 1 to 30 days.
- Prefened amounts of anthelmintic agents such as praziquantel or morantel include, for example, from about 0.5 mg/kg to about 7.5 mg/kg of animal body weight, with a range of about 0.5 mg/kg to about 2 mg/kg or 2.5 mg/kg of body weight being especially prefened.
- a most especially prefened amount is about 1.0 mg/kg of animal body weight.
- Prefened ranges for the macrolide compounds include, for example about 0.01 to about 200 mg/kg of animal body weight, with the ranges of about 0.1 to about 50 mg/kg and from about 1 to about 30 mg/kg being especially prefened.
Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EM15880304 | 2004-03-29 | ||
US20937704A | 2004-07-15 | 2004-07-15 | |
US10/892,261 US20060011666A1 (en) | 2004-07-15 | 2004-07-15 | Pipette/applicator |
PCT/US2005/010446 WO2005094330A2 (en) | 2004-03-29 | 2005-03-28 | Pipette/applicator |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1748930A2 true EP1748930A2 (en) | 2007-02-07 |
EP1748930A4 EP1748930A4 (en) | 2012-05-02 |
Family
ID=37575005
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05731101A Withdrawn EP1748930A4 (en) | 2004-03-29 | 2005-03-28 | Pipette/applicator |
Country Status (1)
Country | Link |
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EP (1) | EP1748930A4 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4512475A (en) * | 1983-11-04 | 1985-04-23 | Alberto Federighi | Single or multiple dose container-closure assemblies |
US4867326A (en) * | 1988-08-25 | 1989-09-19 | Cp Packaging | Child resistant cap and tube assembly |
GB2230520A (en) * | 1989-04-12 | 1990-10-24 | Waverley Pharma Ltd | Blow-fill-seal bottles |
US5301837A (en) * | 1992-01-31 | 1994-04-12 | Cp Packaging, Inc. | Child resistant medicament dispenser |
US6260735B1 (en) * | 2000-05-12 | 2001-07-17 | Colgate-Palmolive Company | Uniform dispensing dual chamber sachet |
-
2005
- 2005-03-28 EP EP05731101A patent/EP1748930A4/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4512475A (en) * | 1983-11-04 | 1985-04-23 | Alberto Federighi | Single or multiple dose container-closure assemblies |
US4867326A (en) * | 1988-08-25 | 1989-09-19 | Cp Packaging | Child resistant cap and tube assembly |
GB2230520A (en) * | 1989-04-12 | 1990-10-24 | Waverley Pharma Ltd | Blow-fill-seal bottles |
US5301837A (en) * | 1992-01-31 | 1994-04-12 | Cp Packaging, Inc. | Child resistant medicament dispenser |
US6260735B1 (en) * | 2000-05-12 | 2001-07-17 | Colgate-Palmolive Company | Uniform dispensing dual chamber sachet |
Non-Patent Citations (1)
Title |
---|
See also references of WO2005094330A2 * |
Also Published As
Publication number | Publication date |
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EP1748930A4 (en) | 2012-05-02 |
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