EP2101736A2 - Homogeneous paste and gel formulations - Google Patents
Homogeneous paste and gel formulationsInfo
- Publication number
- EP2101736A2 EP2101736A2 EP07869573A EP07869573A EP2101736A2 EP 2101736 A2 EP2101736 A2 EP 2101736A2 EP 07869573 A EP07869573 A EP 07869573A EP 07869573 A EP07869573 A EP 07869573A EP 2101736 A2 EP2101736 A2 EP 2101736A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- veterinary
- pharmaceutical
- viscosity modifier
- solvent
- paste
- 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- Withdrawn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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- This invention provides for oral homogeneous veterinary pastes and gels which are used in treating, controlling and preventing of endo- and ectoparasite infections in warm- blooded animals, such as birds, horses and household pets.
- This invention further provides for a process of preparing these veterinary pastes and gels and for a method for increasing the bioavailability of the agents contained in the paste or gel in the warm-blooded animal.
- Therapeutic agents are administered to animals by a variety of routes. These routes include, for example, oral ingestion, topical application or parental administration. The particular route selected by the practitioner depends upon factors such as the physiochemical properties of the pharmaceutical or therapeutic agent, the condition of the host, and economic factors.
- one method of formulating a therapeutic agent for oral, topical, dermal or subdermal administration is to formulate the therapeutic agent as a paste or as an injectable formulation and reference is made to US application Ser. No. 09/504,741, filed February 16, 2000, now U.S. Patent 6,787,342, entitled IMPROVED PASTE FORMULATIONS or to Ser. No. 09/346,905, filed July 2, 1999, now U.S. Patent 6,239,112; Ser. No. 09/112,690, filed July 9, 1999 now U.S. Patent 5,958,888 and Ser. No 09/152,775, filed September 14, 1998, now U.S.
- Patent 6,174,540 entitled LONG ACTING INJECTABLE FORMULATIONS CONTAINING HYDROGENATED CASTOR OIL.
- Other methods include placing the therapeutic agent in a solid or liquid matrix for oral delivery.
- anthelmintic agents in order to improve the spectrum of activity; see, e.g., product disclosure for RM® Parasiticide- 10, an anthelmintic paste comprising febantel and praziquantel.
- Macrolide anthelmintic compounds are known in the art for treating endo- and ectoparasite infections in warm-blooded animals.
- Compounds that belong to this class of agents include the avermectin and milbemycin series of compounds. These compounds are potent antiparasitic agents against a wide range of internal and external parasites.
- Avermectins and milbemycins share the same common 16-membered macrocyclic lactone ring; however, milbemycins do not possess the disaccharide substituent on the 13 -position of the lactone ring.
- avermectins and milbemycins are used to treat endoparasites, e.g., round worm infections, in warm-blooded animals.
- the avermectin and milbemycin series of compounds either are natural products or are semi-synthetic derivatives.
- the natural product avermectins 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).
- Avermectins and milbemycins are ineffective against cestodes, such as tapeworms, which also are a common parasite in warm-blooded animals (see, U.S. Patent 6,207,179).
- cestodes such as tapeworms
- tapeworms which also are a common parasite in warm-blooded animals
- Anoplacephala perfoliata in particular (see, e.g., U.S. Patent 6,207,179 or U.S. Patent
- Formulations which administer a combination of two or more anthelmintics are know in the art. These formulations may be in the form of solutions, suspensions, pastes, drenches or pour-on formulations (see, e.g., U.S. Patent 6,165,987 to Harvey or U.S. Patent 6,340,672 to Mihalik). For example, U.S. Patent 4,468,390 to Kitano and U.S.
- Patent 5,824,653 to Beuvry et al. describe anthelmintic compositions for treating nematode and cestode infections in animals, such as horses, that comprise an avermectin or a milbemycin and an isoquinoline compounds, such as praziquantel, to the animal.
- the avermectin or milbemycin compound and the isoquinoline compound are not dissolved in a solvent, which is then dispersed in a semi-solid matrix.
- Patent 6,207,179 to Mihalik relates to anthelmintic paste formulations wherein the avermectin or milbemycin is dissolved in a non-aqueous liquid and pyrantel or morantel, compounds which are in the same class as praziquantel, but are said in the art to be far less effective as praziquantel, are suspended in the liquid.
- These prior patents do not describe a formulation wherein the both the praziquantel and the avermectin or milbemycin are dissolved in a solvent and then dispersed in a carrier matrix.
- Patent 6,165,987 relates to anthelmintic formulations containing praziquantel and at least one avermectin or milbemycin dissolved in glycerol formal, benzyl alcohol and N-methyl-2- pyrrolidone, which may be liquids, pastes or drenches; the amount of praziquantel administered to the animal is always at a dose of more that 2.0 mg per kg of body weight.
- U.S. Patent 6,165,987 provides for pastes which require the presence of two solvents, one for the praziquantel and one for the macrolide compound.
- the present invention provides for a stable paste or gel formulation for a wide range of veterinary and pharmaceutical products.
- the present invention also provides for an improved process to make the inventive paste and gel products.
- This invention provides for oral homogeneous veterinary pastes and gels for the treating, controlling and preventing of endo- and ectoparasite infections in warm-blooded animals, such as birds, horses and household pets, as well as to a process for preparing these formulations.
- the inventive oral veterinary pastes and gels provide for a more effective treatment of parasitic infections in non-human animals since the active ingredients do not interfere with each other, hence increasing the bioavailability in the animal, while still having the benefits of being administered by as a paste or a gel.
- the inventive formulations provide for a formulation that exhibits good chemical and physical stability over the shelf-life of the product.
- the oral veterinary formulations of the invention may exhibit the benefits of both a solution and a formulation that is a paste or a gel.
- the pharmaceutical or veterinary paste formulation of the present invention may comprise:
- the pharmaceutical or veterinary gel formulation of the present invention may comprise:
- buffering system or thickener wherein the buffering system or thickener is sodium carboxymethylcellulose
- solvent optionally a solvent, wherein the solvent is propylene glycol
- viscosity modifier optionally a viscosity modifier, wherein the viscosity modifier is PEG 400.
- the therapeutic agent may comprise an avermectin, advantageously eprinomectin or ivermectin.
- the therapeutic agent may comprise a COX-2 inhibitor, a proton pump inhibitor, advantageously omeprazole, praziquantel or any combination thereof, including one or more avermectins.
- FIG. 1 depicts leverage plots of variables and whole model
- FIG. 2 depicts a prediction profiler. DETAILED DESCRIPTION
- the present invention provides for a stable paste or gel formulation for a wide range of veterinary and pharmaceutical products.
- the present invention also provides for an improved process to make the inventive paste or gel products.
- the paste or gel formulation of the present invention provides for lower percentage of active ingredient with a resulting increase in the percentage of solvent,
- the present invention provides for a pharmaceutical or veterinary paste or gel formulation comprising: (a) an effective amount of a therapeutic agent;
- This invention also provides for a process for preparing a paste or gel formulation comprising the steps of:
- step (a) can be moved to the last step.
- compositions comprising:
- a therapeutic agent selected from the group consisting of insecticides, acaricides, parasiticides, growth enhancers, oil-soluble NSAIDS or a proton pump inhibitor;
- a carrier which is triacetin, a monoglyceride, a diglyceride, or a triglyceride.
- pastes or gels comprising:
- a therapeutic agent selected from the group consisting of avermectins, milbemycins, nordulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridyl methyl derivatives, phenylpyrazoles, COX-2 inhibitors or 2-(2- benzimidazolyl)-pyrimidine derivatives;
- a therapeutic agent selected from the group consisting of avermectins, milbemycins, nordulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridyl methyl derivatives, phenylpyrazoles, COX-2 inhibitors or 2-(2- benzimidazolyl)-pyrimidine derivatives;
- hydrophilic carrier which is triacetin, a monoglyceride, a diglyceride, or a triglyceride.
- the fumed silica is a colloidal silicon dioxide such as CAB-O-SIL (Cabot, TDl 1) or AEROSIL (Degussa, Technical Bulletin Pigments, No. 11 and No. 49)
- the viscosity modifier is a polyethylene glycol such as PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80), polyoxamers (e.g., Pluronic L 81);
- the absorbent is magnesium carbonate, calcium carbonate, starch, or cellulose and its derivatives; and the colorant is titanium dioxide iron oxide, or FD&C Blue #1 Aluminum Lake are most especially preferred.
- the fumed silica is a colloidal silicon dioxide such as CAB-O-SIL (Cabot, TDl 1), advantageously at a concentration of 5% w/w, the viscosity modifier is PEG 400 and the absorbent is magnesium carbonate.
- the viscosity modifier is PEG 300.
- the PEG 300 is at a concentration of about 0.4% w/w.
- the absorbent is magnesium carbonate, in particular a heavy magnesium carbonate.
- the magnesium carbonate is at a concentration of about 2% w/w.
- the colorant is titanium dioxide, in particular E171 titanium dioxide.
- the titanium dioxide is at concentration of about 0.2% w/w.
- the carrier is triacetin.
- the triacetin is at a concentration of up to about 100% w/w depending on the volume of the active substance and other excipients.
- the therapeutic agents which are used in the inventive formulations are those which are known to the practitioner as agents which may be formulated as pastes or gels.
- Classes of therapeutic agents contemplated by the inventive formulations include insecticides, acaricides, parasiticides, growth enhancers, oil-soluble, nonsteroidal anti-inflammatory drugs (NSAIDS), proton pump inhibitors and antibacterial compounds.
- NSAIDS nonsteroidal anti-inflammatory drugs
- avermectins for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazoles, COX-2 inhibitors, 2-(2-benzimidazolyl)- pyrimidines derivatives, depsipeptides (such as emodepside) and macrolide antibiotics.
- the therapeutic agent is a non-steroidal antiinflammatory drug (NSAID), in particular a COX-2 inhibitor.
- NSAID non-steroidal antiinflammatory drug
- the COX-2 inhibitor is firocoxib.
- the firocoxib is at a concentration of about 0.82% w/w.
- Firocoxib is a veterinary COX-2 inhibitor (anti-inflammatory and anti-arthritic) with a primary application in canines.
- Exemplary patents include, but are not limited to, U.S. Patent No, 6,677,373, which covers polymorphic Form B of 3-(cyclopropylmethoxy)-4-[4- (methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan- 2-one and U.S. Patent No. 5,981 ,576, which covers the compound 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl- 5H-furan- 2-one.
- the present invention further encompasses other COX-2 inhibitors in addition to firocoxib.
- cyclooxygenase-2 inhibitor means any pharmaceutically acceptable compound or combination of compounds, including salts, tautomers and prodrugs of such compound or compounds, that inhibits the enzyme cyclooxygenase-2 in the arachidonic acid/prostaglandin pathway.
- cyclooxygenase-2 inhibitors employed in this invention include, but are not limited to, the compounds corresponding to the structural formula:
- A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carbocyclic rings; wherein R 1 is cyclohexyl or phenyl optionally substituted with one, two or three radicals selected from Ci_2 alkyl, Ci_2 haloalkyl, cyano, carboxyl, Ci_2 alkoxycarbonyl, hydroxyl, Ci_ 2 hydroxyalkyl, Ci_ 2 haloalkoxy, amino, Ci_ 2 alkylamino, phenylamino, nitro, Ci_ 2 alkoxy-Ci_ 2 alkyl, Ci_ 2 alkylsulfinyl, halo, Ci_ 2 alkoxy and Ci_ 2 alkylthio; wherein R 2 is methyl or amino; wherein R 3 is a radical selected from halo, Ci_2 alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, hetero
- A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carbocyclic rings selected from the group consisting of thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl; wherein R 1 is cyclohexyl or phenyl optionally substituted with one, two or three radicals selected from Ci_2 alkyl, halo, and Ci_ 2 alkoxy; wherein R 2 is methyl or amino; wherein R 3 is a radical selected from halo, Ci_ 2 alkyl, oxo, cyano, carboxyl, Ci_ 2 alkyloxy,
- the COX-2 inhibitor is 3-
- COX-2 inhibitors that may be employed in the present invention include, but are not limited to, lomoxicam, l,5-diphenyl-3-substituted pyrazoles, radicicol, N-benzyl-3- indoleacetic acids, the inhibitors of GB-02283745, TP-72, indene inhibitors of COX-2, carbocyclic diarylmethylene derivatives, 1,2-diarylindole, 1 ,2-bisarylcyclobutene derivatives, novel stilbene derivatives as prodrug forms of the diphenylcyclopentenonees of US- 05474995, WO-09500501 and WO-09518799, 2,4-diphenylbutenoic acid derivatives as prodrugs of COX-2 inhibitors claimed in US-05474995, WO-09500501 and WO-09518799, l-(4-chlorobenzoyl)-3-[4-(4-fluorophenyl)thia
- COX-2 inhibitors that may be employed in the present invention include, but are not limited to, the COX-2 inhibitors disclosed in AT 9700165, AU 9719132 , CA 2164559, DE 19518421, DE 19533643, DE 19533644, DE 19753463, EP 714895, EP 799823 , EP 832652, EP 846689, EP 850894, EP 850895, EP 95909447.5, EP 95928164.3 , FR 2751966, GB 2283745, GB 2294879, GB 2319772, GB 2320715, JP 08157361, JP 09048769, JP 09071656, JP 09071657, JP 09077664, JP 09194354, JP 09221422, JP
- COX-2 inhibitors are selected from the group consisting of:
- cyclooxygenase-2 inhibitors are selected from the group consisting of:
- Compounds which inhibit gastric acid secretion in the stomach or act as proton pump inhibitors are well known to the practitioner and are also provided for in the present invention. These compounds include 2-(2-benzimidazolyl-pyridines) and their salts. Such compounds are described, for example in EP 005 129, U.S. Pat. No. 4,255,431 as well as in U.S. Pat. No. 5,629,305. These compounds are also known to treat Helicobacter infections, U.S. Pat. No. 5,093,342, and to act as synergists when combined with an acid degradable antibiotic, see e.g. U.S. Pat. No. 5,629,305. These synergistic combinations may also be formulated in the pastes of the present invention. Omeprazole or its salts is an especially preferred compound.
- the proton pump inhibitors used in the present invention can include compounds of the general formula: wherein R 3 is
- R 1 and R 3 are independently selected from from hydrogen, lower alkyl, lower alkoxy and halogen
- R 2 is selected from hydrogen, lower alkyl, lower alkoxy-lower alkoxy, lower fluoralkoxy and
- R 4 and R 5 are independently selected from lower alkyl
- R 6 and R 7 are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen,
- R.sup.8 is lower alkyl or lower alkoxy.
- proton pump inhibitors include:
- PPI examples include esomeprazole (nee: perprazole), rabeprazole, and IY- 81149 (distributed by Axican Pharma).
- the preferred proton pump inhibitor used in the present invention is the compound known as omeprazole.
- omeprazole is disclosed in EP 5129, lansoprazole in EP 174.716, pantoprazole in EP 166,287, leminoprazole in GB 2,163,747, rabeprazole in U.S. Pat. No. 5,045,552.
- the present invention also provides for an oral homogeneous anthelmintic veterinary paste or gel, for the treating, controlling and preventing of endo-and ectoparasite infections in warm-blooded animal, which comprises an anthelmintic agent, such a praziquantel, and/or pyrantel and, as a second agent, at least one macro lide anthelmintic agent, a solvent which dissolves both the first anthelmintic agent and the macrolide anthelmintic agent, and a thickening agent.
- an anthelmintic agent such a praziquantel, and/or pyrantel
- a second agent at least one macro lide anthelmintic agent, a solvent which dissolves both the first anthelmintic agent and the macrolide anthelmintic agent, and a thickening agent.
- this invention provides for an oral homogeneous veterinary paste or gel consisting essentially of praziquantel and/or pyrantel and at least one macrolide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, and at least one thickening agent.
- oral homogeneous veterinary pastes or gels consisting essentially of praziquantel and/or pyrantel and at least one macrolide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, at least one thickening agent, and at least one viscosity modifier.
- Another embodiment of the invention is an oral veterinary composition consisting essentially of the inventive oral homogeneous veterinary pastes or gels and an opacifier.
- inventive oral homogeneous veterinary pastes or gels provide for the combination of at least two different anthelmintic agents, one of which is a macro lide anthelmintic compound.
- the classes of compounds encompassed by the first agent are well known to practitioners in this art. These compounds include, in addition to praziquantel and its related compounds, anthelmintic agents such as pyrantel (see, U.S. Patent 3,502,661 for a description of pyrantel and its related compounds).
- the invention provides for an oral homogeneous veterinary paste or gel consisting essentially of praziquantel and/or pyrantel and at least one macro lide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, at least one thickening agent, and at least one viscosity modifier.
- the macrolide anthelmintic compound is selected from the group consisting of doramectin, abamectin, moxidectin, selamectin and ivermectin;
- the solvent is glycerol formal, propylene glycol, n-methylpyrrolidone, or dimethyl sulfoxide;
- the thickening agent is selected from the group consisting of a cellulose, a starch, monothioglycerol, polymers or copolymers of polyvinylpyrrolidone, polymers and copolymers of
- (meth)acrylate, and a natural gum and the viscosity modifier is selected from the group consisting of vegetable oils, or hydrogenated vegetable oils.
- the thickening agent is hydroxypropylcellulose, xanthum gum or hydroxyethyl starch and the viscosity modifier is hydrogenated castor oil, corn oil or olive oil.
- the macrolide anthelmintic compounds contemplated in this invention are also well known to a practitioner of this area. These compounds include avermectins and milbemycins, some of which are 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
- R 6 is hydroxy, amino, mono-or di-lower alkylamino or lower alkanoylamino.
- the preferred compounds are avermectin Bla/Blb (abamectin), 22,23-dihydro avermectin Bla/Blb (ivermectin) and the 4"-acetylamino-5-ketoximino derivative of avermectin Bla/Blb. Both abamectin and ivermectin are approved as broad spectrum antiparasitic agents.
- abamectin and ivermectin are as follows:
- 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 R 2 is isopropyl.
- avermectin examples include emamectin, eprinomectin and doramectin.
- Doramectin is disclosed in U.S. Patent 5,089,490 and EP 214 738. This compound has the following structure:
- ivermectin is especially preferred.
- a representative structure for a milbemycin is that for milbemycin (X 1 :
- milbemycin is moxidectin, whose structure is as follows:
- the compound is disclosed in U.S. Patent No. 5,089,490.
- the monosaccharide avermectin derivatives are also preferred 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.
- Selamectin is an especially preferred compound of this class of derivatives.
- 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.
- Preferred acids are straight chain or branched, saturated or unsaturated C1-C20 aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C 6 -Ci 2 aromatic carboxylic acids.
- Examples of such 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.
- 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. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid.
- Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.
- 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 ester and amide derivatives of these compounds are also contemplated.
- Specific compounds which belong to this class of macro lide antiparasitic agents are well known to the practitioner of this art.
- the solvents provided for in the inventive homogeneous pastes or gels are those polar solvent that will dissolve both the first anthelmintic agent and the macrolide anthelmintic compound.
- These solvents include, for example, glycerol formal, 1-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO).
- NMP 1-methylpyrrolidone
- DMSO dimethyl sulfoxide
- thickeners contemplated by this invention are well known to a practitioner of this art.
- Compounds which function as thickeners include, for example, celluloses, starches, natural gums, monothioglycerol, synthetic polymers, such as polymers and copolymers of polyvinylpyrrolidone or (meth)acrylates, etc.
- Especially preferred thickeners are sodium carboxymethylcellulose (CMC), hydroxypropylcellulose, xanthum gum and hydroxyethyl starch.
- Thickeners may be present in amounts of from about 3 % to about 30 %.
- the thickener is silica, in particular an anhydrous silica, even more particularly a colloidal anhydrous silica.
- the colloidal anhydrous silica is at a concentration of about 4.5 % w/w.
- 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 preferred. These compounds are well known to practitioners of this art.
- inventive formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers.
- antioxidants such as an alpha tocopheral, ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol and the like, may be added to the present formulation.
- 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 preferred.
- 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 preferred.
- Other 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. Preferred ranges for these compounds include from about 0.01 to about 5 %.
- Colorants may be added to the inventive formulations.
- Colorants contemplated by the present invention are those commonly known in the art. Specific colorants include, for example, dyes, an aluminum lake, caramel, colorant based upon iron oxide or a mixture of any of the foregoing. Especially preferred are organic dyes and titanium dioxide. Preferred ranges include from about 0.5 % to about 25 %.
- Buffering systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates, sodium carbonate and sodium carboxymethylcellulose (CMC).
- Preferred ranges for pH include from about 4 to about 6.5.
- the present invention also encompasses flavorings.
- the flavoring may be a mint flavor, fruit flavor, an herb flavor or a spice flavor.
- Mint flavors include, but are not limited to peppermint, spearmint and wintergreen.
- Fruit flavors include, but are not limited to, apple, apricot, banana, blackberry, blueberry, cherry, Clementine, coconut, cranberry, currant, grape, grapefruit, huckleberry, juniper berry, kiwifruit, lemon, lime, mandarin, melon, orange, papaya, peach, pear, pineapple, plum, pomegranate, raspberry, strawberry, tangerine and watermelon flavors.
- Herb and/or spice flavors include, but are not limited to, allspice, ancho chile, anise, basil, bay leaf, black pepper, black walnut, caraway seed, cardamom, celery seed, chai-tea, chamomile, chervil, chickory, chipotle chile, chives, cilantro, cinnamon, citrus ginger, clove, coriander, cumin, dill, elderflower, fennel, ginger, ginseng, guarana, hot pepper, jalapeno, Jamaica, jasmine, lavender, lemon grass, licorice, mace, marjoram, mint, mustard, nutmeg, oregano, paprika, parsley, poppy seed, pure vanilla, red pepper, rose, rosemary, saffron, sage, savory, sesame seed, tamarind, tarragon, tea, teaberry, thyme, turmeric, vanilla and white pepper.
- the flavors may be natural or artificial.
- the flavoring is a peppermint flavor or an apple flavor, advantageously an artificial apple flavor.
- the flavoring is a cinnamon flavor.
- the inventive pastes or gels may be administered to warm-blooded animals.
- Warmblooded animals include, for example, all ruminants, equines, canines, felines and avians. Especially preferred are birds, cattle, sheep, pigs, dogs, cats, horses and the like.
- the amount of each of anthelmintic compounds is well known to a practitioner of this art.
- Preferred amounts of praziquantel 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 preferred.
- a most especially preferred amount is about 1.0 mg/kg of animal body weight.
- Preferred ranges for the anthelmintic 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 preferred.
- inventive oral homogeneous pastes may be prepared, for example, by a process which comprises:
- More preferred processes comprise: — dissolving the at least two different anthelmintic agents, e.g., praziquantel or pyrantel, and macrolide anthelmintic compound or compounds, and thickening agent or agents into the solvent and forming a thickened solution;
- anthelmintic agents e.g., praziquantel or pyrantel
- macrolide anthelmintic compound or compounds dissolving the at least two different anthelmintic agents, e.g., praziquantel or pyrantel, and macrolide anthelmintic compound or compounds, the thickening agent or agents and least one compound selected from the group consisting of an antioxidant, a colorant, a pH stabilizer and/or a preservative into the solvent and forming a thickened solution;
- a preferred process to prepare the inventive oral veterinary compositions comprises:
- inventive oral veterinary formulations may be used to treat a number of ecto-and endoparasite infections.
- the determining of a treatment protocol for an infection of a specific parasite or parasites would be well within the skill level of a practitioner of the veterinary art.
- This invention further provides for a method to increase the bioavailability of the at least two different anthelmintic agents in the animal. The invention will now be further described by way of the following non- limiting examples.
- Example 1 Oral Veterinary Homogeneous Paste
- HPC Hydroxypropylcellulose
- Stabilized glycerol formal QS AD 100 was prepared by the following process:
- a stock solution of active in triacetin was prepared.
- titanium dioxide, magnesium carbonate (light or heavy), and 4% w/w or 5% w/w colloidal silicon dioxide was added using a Lightnin mixer with an appropriate size impeller.
- the mixer speed was set at either 300 rpm (low shear) or 800 rpm (high shear) and the beaker was set in a circulating water bath maintained at either 25 C or 45 C according to the requirements of the experimental run.
- remaining triacetin and viscosity modifier PEG 300 or PEG 400
- Paste was removed from the beaker and approximately 8 grams was centrifuged at 15,000 rpm for 15 minutes and the resulting supernatant liquid was weighed.
- Table 1 Design of Experiments and their results
- the leverage plots are provided for each of the variable factors as well as the whole model as shown in FIG. 1.
- the strength of the effect is shown by the slope of the central fit line. The greater the slope (positive or negative), the greater the effect that variable has on the paste separation.
- the distance from each point to the central fit line is what the error would be if the variable is taken out of the model. Confidence curves on the graph show whether an effect is significant or not. If the 95% confidence curves cross from the horizontal reference line, then the effect is significant; if the curves do not cross, then it is not significant.
- An oral paste for horses contains firocoxib as active substance, a non-steroidal antiinflammatory drug (NSAID) that reduces prostaglandin biosynthesis through the selective inhibition of cyclooxygenase-2 (COX-2).
- NSAID non-steroidal antiinflammatory drug
- the intended indication in horses is the alleviation of pain and inflammation in animals with ortheoarthritis and reduction of associated lameness.
- the intended therapeutic dose in horses is 0.1 mg firocoxib/kg bw/day orally for up to 14 consecutive days.
- the 0.82% oral paste for horses is presented in pre-filled oral syringes containing 7.32 g of oral paste labelled in 100-kg dosing increments. Each syringe contains sufficient product to treat a 600 kg horse.
- early formulations contained active substance concentrations ranging from 0.41 - 2.05 %.
- the final active substance concentration was chosen with reference to the dose (0.1 mg/kg) and convenience of administration to horses up to 600 kg bodyweight in plastic syringes which are widely used for this dosage form.
- the active substance is poorly soluble in water and triacetin was the vehicle of choice because of its ability to solubilise firocoxib and the stability of the resultant solutions under accelerated conditions. Because the active substance is dissolved in the vehicle, particle size and polymorphic properties of the active substance are not relevant to the bioavailability of the formulation.
- several viscosity modifying agents, in combination with colloidal silicon dioxide were investigated. Formulations containing combinations of colloidal silicon dioxide, monoethanolamine and polyethylene glycol 300 (PEG 300) were investigated for viscosity, manageability and penetration values.
- Triacetin colloidal silicon dioxide, polyethylene glycol
- titanium dioxide and magnesium carbonate are all monographed in the Ph.Eur. and are generally regarded as non-toxic and non-irritant materials.
- Magnesium carbonate is widely used to adsorb liquids at a concentration of 0.5-1.0 %.
- the paste contains 2 % of magnesium carbonate, which is already above the typical concentration range.
- the paste contains 4.5 % colloidal silicon dioxide which is typically used at concentrations ranging 2-10 % as a suspending and thickening agent in semi-solid preparations. Hence it was decided to increase the concentration of colloidal silicon dioxide rather than magnesium carbonate. Additionally, formulations with 4 % magnesium carbonate showed lower penetration values (higher viscosity) as compared to formulations with 2 % magnesium carbonate. It is important that a minimum penetration value specification of 6 mm be maintained for proper flow characteristics and there is an increased risk that the penetration value would not meet this specification throughout shelf life of the product if higher levels of magnesium carbonate were utilised.
- Example 4 A Palatable Oral Gel dosage Form Containing Eprinomectin for Horses
- a clear gel formulation containing eprinomectin was developed as an oral dosage form for horses and ponies for the treatment of internal parasites.
- the gel formulation can be administered directly from a syringe onto the horse's tongue.
- an oral gel formula provides improved consistency in delivering the dose as compared to suspensions or paste. Manufacturability is simpler than suspensions or pastes.
- Table 4 Examples of components and compositions of an oral gel formultation:
- the formulation was prepared by first dissolving eprinomectin in propylene glycol or polyethylene glycol. This solution is added to a dispersion of sodium carboxymethylcellulose (Na-CMC) in water. The liquid flavor, sodium ascorbate and potassium sorbate are added and mixed until a clear homogenious system is obtained.
- Na-CMC sodium carboxymethylcellulose
- oral gel formulation While the examples above were carried out with eprinomectin, other active ingredients would be expected to provide similar results in oral gel formulation.
- Other gelling agents such as xanthan gum, citrus pectin, sodium alginate, poloxamers, carbomers as well as other cellulose gums can also be utilized in the formulation.
- the oral gel formulation is also suited for use in swine, sheep and cattle.
- An oral homogeneous veterinary paste consisting essentially of praziquantel and/or pyrantel and at least one macrolide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, and at least one thickening agent.
- An oral homogeneous veterinary paste consisting essentially of praziquantel and/or pyrantel and at least one macrolide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, at least one thickening agent, and at least one viscosity modifier.
- An oral homogeneous veterinary paste consisting essentially of praziquantel and/or pyrantel and at least one macrolide anthelmintic compound, a solvent, which dissolves both the praziquantel and/or pyrantel and the macrolide anthelmintic compound, at least one thickening agent, a viscosity modifier and at least one compound selected from the group consisting of an antioxidant, a colorant, a pH stabilizer and a preservative.
- An oral veterinary composition consisting essentially of an oral homogeneous veterinary paste according to any one of paragraphs 1 to 3 and an opacif ⁇ er.
- the macro lide anthelmintic compound is selected from the group consisting of doramectin, abamectin, moxidectin, selamectin, eprinomectin and milbemycin;
- the solvent is glycerol formal, propylene glycol, 1-methylpyrrolidone, or dimethyl sulfoxide;
- the thickening agent is selected from the group consisting of a cellulose, a starch, monothioglycerol, a natural gum, a polymer or copolymer of polyvinylpyrrolidone, and a polymer or copolymer of (meth)acrylate.
- An oral veterinary composition consisting essentially of an oral homogeneous veterinary paste according to paragraph 7 and an opacif ⁇ er.
- the macrolide anthelmintic compound is ivermectin.
- the macrolide anthelmintic compound is selected from the group consisting of doramectin, abamectin, moxidectin, selamectin, eprinomectin and milbemycin;
- the solvent is glycerol formal, propylene glycol, n-methylpyrrolidone, or dimethyl sulfoxide;
- the thickening agent is selected from the group consisting of a cellulose, a starch, monothioglycerol, polymers or copolymers of polyvinylpyrrolidone, polymers and copolymers of (meth)acrylate, and a natural gum;
- the viscosity modifier is selected from the group consisting of vegetable oils, or hydrogenated vegetable oils.
- An oral veterinary composition consisting essentially of an oral homogeneous veterinary paste according to paragraph 11 and an opacifier.
- the thickening agent is hydroxypropylcellulose, xanthum gum or hydroxyethyl starch and the viscosity modifier is hydrogenated castor oil, corn oil or olive oil and the opacifier is selected from the group consisting of titanium dioxide and zinc oxide.
- the macrolide anthelmintic compound is ivermectin and the opacifier is titanium dioxide.
- the macrolide anthelmintic compound is selected from the group consisting of doramectin, abamectin, eprinomectin, moxidectin, selamectin and milbemycin;
- the solvent is glycerol formal, propylene glycol, n-methylpyrrolidone, or dimethyl sulfoxide;
- the thickening agent is selected from the group consisting of a cellulose, a starch, monothioglycerol, polymers or copolymers of polyvinylpyrrolidone, polymers or copolymers of (meth)acrylate, and a natural gum;
- the viscosity modifier is selected from the group consisting of vegetable oils and hydrogenated vegetable oils.
- the antioxidant is selected from the group consisting of alpha tocopherol, ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n- propyl gallate, butylated hydroxy anisole, butylated hydroxy toluene, monothioglycerol;
- the colorant is dye, an aluminum lake, caramel, and colorant based upon iron oxide
- the pH stabilizer is a buffering system selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate;
- the preservative is a compound selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, centrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, propylparaben, phenol, phenoxyethanol, phenylethyl, alcohol, phenylmercuric acetate, pheylmecuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, and thimerosal. 18.
- the macrolide anthelmintic compound is ivermectin.
- the macrolide anthelmintic compound is ivermectin
- the solvent is glycerol formal
- the thickener is hydroxypropylcellulose
- the viscosity modifier is hydrogenated castor oil
- the colorant is an organic dye
- the preservative is selected from the group consisting of butylated hydroxytoluene or butylated hydroxy anisole.
- the oral veterinary composition consisting essentially of a an oral homogeneous veterinary paste according to paragraph 17 and an opacifier.
- the oral veterinary composition consisting essentially of an oral homogeneous veterinary paste according to paragraph 19 and an opacifier.
- a process for preparing an oral homogeneous veterinary paste according to paragraph 3 which comprises:
- a process for preparing an oral veterinary composition according to paragraph 4 which comprises: —dissolving the parzequantel and at least one macrolide anthelmintic compound or compounds and the thickening agent or agents into the solvent and forming a thickened solution;
- a method for increasing the bioavailability of praziquantel and at least one macrolide anthelmintic compound in a warm-blooded animal which comprises administering the oral homogeneous veterinary paste according to any one paragraphs 1 to 3 said warmblooded animal or bird.
- a method for increasing the bioavailability of praziquantel and at least one macrolide anthelmintic compound in a warm-blooded animal or bird which comprises administering the oral veterinary composition according to paragraph 4 to said warm-blooded animal or bird.
- An oral veterinary paste consisting essentially of dissolved praziquantel and dissolved ivermectin.
- 34 The oral veterinary paste of paragraph 33 wherein the praziquantel and ivermectin are both dissolved in glycerol formal.
- the oral veterinary paste of paragraph 34 further consisting essentially of praziquantel and ivermectin dissolved in glycerol formal and a cellulose.
- the oral veterinary paste of paragraph 35 further consisting essentially of hydrogenated caster oil.
- the oral veterinary paste of paragraph 36 further consisting essentially of antioxidant, colorant, titanium dioxide.
- the oral veterinary paste of paragraph 33 further consisting essentially of a cellulose, hydrogenated castor oil, and glycerol formal.
- the oral veterinary paste of paragraph 33 further consisting essentially of a cellulose, hydrogenated castor oil, glycerol formal and one or more compounds selected from the group consisting of an antioxidant, an opacif ⁇ er and a colorant.
- a method for increasing the bioavailability of praziquantel and a macro lide anthelmintic compound in a warm-blooded animal which comprises administering the oral veterinary paste according to paragraph 33 to said warm-blooded animal.
- the oral veterinary paste of paragraph 50 which is produced by the process comprising: (a) dissolving praziquantel, ivermectin, colorant, titanium dioxide, antioxidant and cellulose into glycerol formal to form a thickened solution;
- the oral veterinary paste according to paragraph 50 which is praziquantel 7.75 (% w/w) ivermectin 1.55 (% w/w) butylated hydroxyanisole 0.02 (% w/w) sunset yellow (FD&C Yellow No. 6) 0.04 (% w/w) titanium dioxide 2.0 (% w/w) hydroxypropylcellulose 6.0 (% w/w) hydrogenated castor oil 4.0 (% w/w) glycerol formal QS AD 100.
- An oral veterinary paste comprising: praziquantel 7.75 (% w/w) ivermectin 1.55 (% w/w) hydroxypropylcellulose 6.0 (% w/w) hydrogenated castor oil 4.0 (% w/w) glycerol formal QS AD 100 and optionally, one or more compounds selected from the group consisting of an antioxidant, an opacif ⁇ er and a colorant.
- the antioxidant is butylated hydroxyanisole
- the opacif ⁇ er is titanium dioxide and the colorant is sunset yellow (FD&C Yellow No. 6).
- a method for increasing the bioavailability of praziquantel and a macro lide anthelmintic compound in a warm-blooded animal which comprises administering the oral veterinary paste according to paragraph 50 to said warm-blooded animal.
- a method for preparing a pharmaceutical or veterinary paste formulation comprising: dissolving or dispersing a therapeutic agent into a carrier, adding fumed silica and an absorbent to the carrier containing the dissolved therapeutic agent, mixing the fumed silica, absorbent and carrier containing the dissolved therapeutic agent at low shear, maintaining the temperature at about 25 C until the silica and absorbent is dispersed in the carrier and adding a viscosity modifier to the intermediate with mixing to produce a uniform pharmaceutical or veterinary paste formulation.
- the magnesium carbonate is a light magnesium carbonate.
- the colloidal silicon dioxide is at a final concentration of 5% w/w in the pharmaceutical or veterinary paste formulation and the magnesium carbonate is a light magnesium carbonate.
- a pharmaceutical or veterinary paste formulation comprising: (a) an effective amount of a therapeutic agent,
- the therapeutic agent is selected from the group consisting of avermectins, milbemycins, nordulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridyl methyl derivatives, phenylpyrazoles, COX-2 inhibitors or 2-(2-benzimidazolyl)-pyrimidine derivatives.
- the pharmaceutical or veterinary paste of paragraph 72 further comprising a colorant, stabilizer, surfactant or preservative.
- a pharmaceutical or veterinary paste formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is a COX-2 inhibitor,
- viscosity modifier (e) a viscosity modifier, wherein the viscosity modifier is PEG 300.
- a pharmaceutical or veterinary paste formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is a firocoxib,
- a thickener wherein the thickener is colloidal anhydrous silica
- a viscosity modifier wherein the viscosity modifier is PEG 300
- a pharmaceutical or veterinary paste formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is about 0.82%w/w firocoxib,
- a pharmaceutical or veterinary gel formulation comprising:
- antioxidant wherein the antioxidant is sodium ascorbate
- buffering system or thickener wherein the buffering system or thickener is sodium carboxymethylcellulose.
- a pharmaceutical or veterinary gel formulation comprising:
- antioxidant wherein the antioxidant is sodium ascorbate
- a preservative wherein the preservative is potassium sorbate
- a flavoring wherein the flavoring is a peppermint or apple flavor
- buffering system or thickener wherein the buffering system or thickener is sodium carboxymethylcellulose.
- the pharmaceutical or veterinary gel formulation of paragraph 105 further comprising a solvent, wherein the solvent is propylene glycol.
- the pharmaceutical or veterinary gel formulation of paragraph 105 further comprising a viscosity modifier, wherein the viscosity modifier is polyethylene glycol.
- polyethylene glycol is about 20.0% w/w.
- a pharmaceutical or veterinary gel formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is about 0.050% w/w eprinomectin,
- antioxidant wherein the antioxidant is about 1.0% w/w sodium ascorbate
- a preservative wherein the preservative is about 0.5% w/w potassium sorbate
- a flavoring wherein the flavoring is about 1.0% w/w peppermint or about
- a buffering system or thickener wherein the buffering system or thickener is about 3.9% w/w sodium carboxymethylcellulose.
- the pharmaceutical or veterinary gel formulation of paragraph 116 further comprising a solvent, wherein the solvent is about 20.0% w/w propylene glycol.
- the pharmaceutical or veterinary gel formulation of paragraph 116 further comprising a viscosity modifier, wherein the viscosity modifier is about 20.0% polyethylene glycol 400.
- a pharmaceutical or veterinary gel formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is ivermectin,
- antioxidant wherein the antioxidant is sodium ascorbate
- a flavoring wherein the flavoring is a peppermint or apple flavor and (e) a buffering system or thickener, wherein the buffering system or thickener is sodium carboxymethylcellulose.
- a pharmaceutical or veterinary gel formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is a proton pump inhibitor,
- antioxidant wherein the antioxidant is sodium ascorbate
- a flavoring wherein the flavoring is a peppermint or apple flavor and (e) a buffering system or thickener, wherein the buffering system or thickener is sodium carboxymethylcellulose.
- a pharmaceutical or veterinary gel formulation comprising: (a) an effective amount of a therapeutic agent, wherein the therapeutic agent is a COX-2 inhibitor,
- antioxidant wherein the antioxidant is sodium ascorbate
- a preservative wherein the preservative is potassium sorbate
- a flavoring wherein the flavoring is a peppermint or apple flavor
- buffering system or thickener wherein the buffering system or thickener is sodium carboxymethylcellulose.
- compositions of any one of paragraphs 119 to 124 further comprising a solvent, wherein the solvent is propylene glycol.
- the pharmaceutical or veterinary gel formulation of any one of paragraphs 119 to 125 further comprising a viscosity modifier, wherein the viscosity modifier is polyethylene glycol 400.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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PCT/US2006/048672 WO2007075827A2 (en) | 2005-12-20 | 2006-12-19 | Homogeneous paste formulations |
US11/713,881 US20080027011A1 (en) | 2005-12-20 | 2007-03-05 | Homogeneous paste and gel formulations |
PCT/US2007/088225 WO2008077130A2 (en) | 2006-12-19 | 2007-12-19 | Homogeneous paste and gel formulations |
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EP2101736A2 true EP2101736A2 (en) | 2009-09-23 |
EP2101736A4 EP2101736A4 (en) | 2012-09-19 |
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EP07869573A Withdrawn EP2101736A4 (en) | 2006-12-19 | 2007-12-19 | Homogeneous paste and gel formulations |
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CA (1) | CA2673193C (en) |
MX (1) | MX2009006656A (en) |
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CA3087822C (en) * | 2018-01-18 | 2022-08-02 | Zoetis Broomhill Ip Limited | Internal teat sealants and their use in the prevention of bovine mastitis in the dry cow |
US10857151B1 (en) * | 2020-02-21 | 2020-12-08 | Villya LLC | Treatment of female genital schistosomiasis |
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US20040151759A1 (en) * | 2002-08-16 | 2004-08-05 | Douglas Cleverly | Non-animal product containing veterinary formulations |
US20050158252A1 (en) * | 2003-12-22 | 2005-07-21 | Radek Romanowski | Method and compositions for oral hygiene |
EP1848270B1 (en) * | 2005-02-17 | 2014-05-21 | Abbott Laboratories | Transmucosal administration of drug compositions for treating and preventing disorders in animals |
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- 2007-12-19 MX MX2009006656A patent/MX2009006656A/en not_active Application Discontinuation
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